Compounds and methods for kinase modulation, and indications therefor

ABSTRACT

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described, wherein the compounds have formula Ia: 
     
       
         
         
             
             
         
       
     
     In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC kinase protein. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of one or more of Fms, Kit, Flt3, TrkA, TrkB and TrkC, including rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer&#39;s disease, Parkinson&#39;s disease, global ischemia, ulcerative colitis, Crohn&#39;s disease, immune thrombocytopenic purpura, atherosclerosis, systemic lupus erythematosis, myelopreparation for autologous transplantation, transplant rejection, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastoma, neurofibromatosis, osteolytic bone metastases, brain metastases, gastrointestinal stromal tumors, and giant cell tumors.

CROSS-REFERENCE TO RELATED PATENT APPLICATION

This application is a divisional application of U.S. application Ser.No. 14/556,709 filed Dec. 1, 2014, which is a continuation of U.S.application Ser. No. 13/090,969 filed Apr. 20, 2011, now U.S. Pat. No.8,901,118, which claims the benefit of U.S. Provisional Application61/326,626, filed Apr. 21, 2010, the entire disclosures of which areincorporated herein by reference.

FIELD OF THE INVENTION

Disclosed are novel compounds and uses thereof. In certain embodimentsdisclosed compounds are kinase inhibitors.

SUMMARY OF THE INVENTION

In certain aspects and embodiments disclosed herein, compounds areprovided, as well as various salts thereof, formulations thereof,conjugates thereof, derivatives thereof, forms thereof and uses thereof.In certain embodiments, the compounds are active on one or more proteinkinases, including Fms, Kit, Flt3, TrkA, TrkB and/or TrkC, including anymutations thereof. In certain embodiments, compounds are active on Fmskinase. In certain embodiments, compounds are active on Fms and Kitkinase. In certain embodiments, compounds are selectively active on Fmskinase relative to Kit kinase. In certain embodiments, compounds areactive on Fms kinase and Flt3 kinase. In certain embodiments, compoundsare active on Fms kinase and one or more of TrkA, TrkB and TrkC kinase.

Also contemplated in accordance with the present invention are methodsfor the use of the compounds in treating diseases and conditionsassociated with regulation of the activity of one or more of Fms, Kit,Flt3, TrkA, TrkB and TrkC, including any mutations thereof. Thus, theuse of compounds for therapeutic methods involving modulation of proteinkinases are provided. In certain embodiments, the compounds are used fortherapeutic methods involving the treatment of a variety of indications,including, but not limited to, rheumatoid arthritis, osteoarthritis,osteoporosis, peri-prosthetic osteolysis, systemic sclerosis,demyelinating disorders, multiple sclerosis, Charcot Marie Toothsyndrome, amyotrophic lateral sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, ulcerative colitis, Crohn'sdisease, immune thrombocytopenic purpura, atherosclerosis, systemiclupus erythematosis, myelopreparation for autologous transplantation,transplant rejection, glomerulonephritis, interstitial nephritis, Lupusnephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy,type I diabetes, acute pain, inflammatory pain, neuropathic pain, acutemyeloid leukemia, melanoma, multiple myeloma, breast cancer, prostatecancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas,glioblastoma, neurofibromatosis, osteolytic bone metastases, brainmetastases, gastrointestinal stromal tumors, and giant cell tumors. Insome embodiments, compounds are of Formula I as described below.

In a first aspect, compounds having the structure according to thefollowing Formula I are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   X₁ is —N═, —C(H)═, or —C(R¹)═;    -   Y₁ is —N═ and R³ is hydrogen; or Y₁ is —C(H)═ and R³ is fluoro        or chloro;    -   L₁ is —C(H₂)— or —C(O)—;    -   Cy₁ is cycloalkyl optionally substituted with one or more R⁴,        phenyl optionally substituted with one or more R⁵, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁶ and optionally substituted on an        available nitrogen atom with R⁷;    -   when X₁ is —C(R¹)═, R² is hydrogen;    -   when X₁ is —N═ or —C(H)═, R² is selected from the group        consisting of hydrogen, cycloalkyl, lower alkyl optionally        substituted with one or more R⁸, —N(R^(9a))(R^(9b)), and —O—R⁹;    -   R¹ is fluoro, chloro, or lower alkyl optionally substituted with        one or more fluoro;    -   each R⁴ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁵ is independently selected from the group consisting of        fluoro, chloro, —O—R¹⁰, —S—R¹¹, —S(O₂)—R¹², and lower alkyl        optionally substituted with one or more R¹³;    -   each R⁶ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁶ bound to adjacent        carbon atoms of the heteroaryl ring, taken together, form a        fused cycloalkyl ring;    -   R⁷ is cycloalkyl, lower alkoxy or lower alkyl optionally        substituted with one or more fluoro;    -   R⁸ is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R^(9a) is H and R^(9b) is selected from the group consisting        of (i) H, lower alkyl, lower alkyl substituted with one or more        fluoro, lower alkyl substituted with lower alkoxy or lower alkyl        substituted with hydroxyl and (ii) cycloalkyl, cycloalkylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, arylalkyl,        heteroarylalkyl, each of which is optionally substituted with        one to three members selected from lower alkyl, haloalkyl, lower        alkoxy or fluoro; or    -   R^(9a) and R^(9b) together with the nitrogen to which they are        attached form a 5- or 6-membered ring having from 0 to 1        additional heteroatom selected from O, N or S, each of which is        optionally substituted with one to three members selected from        lower alkyl, haloalkyl, lower alkoxy or fluoro;    -   R⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R¹⁰, R¹¹ and R¹² are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹³ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.        In some embodiments of compounds of Formula I, R³ is fluoro. In        certain embodiments, the salt is a pharmaceutically acceptable        salt.

In some embodiments, the invention provides compounds of Formula I orany of the subformulas as described herein, or a pharmaceuticallyacceptable salt, a solvate, a tautomer or a stereoisomer thereof. Inother embodiments of the invention, there are provided compounds ofFormula I or any of the subformulas as described herein, or apharmaceutically acceptable salt or a solvate thereof. In someembodiments, the solvate is a hydrate.

In some embodiments of compounds of Formula I, X₁ is —N═ and R² isselected from the group consisting of cycloalkyl, lower alkyl optionallysubstituted with one or more R⁸, for example, 1 to 3 R⁸, and —O—R⁹. Inone embodiment, X₁ is —N═ and R² is selected from the group consistingof cycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substitutedwith lower alkoxy. In one embodiment, X₁ is —N═ and R² is selected fromthe group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, andC₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, X₁ is —N═and R² is selected from the group consisting of methyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, and2-methoxy-ethoxy.

In some embodiments of compounds of Formula I, X₁ is —C(H)═ or —C(R¹)═and R¹ is fluoro, chloro, or lower alkyl optionally substituted with oneor more fluoro. In one embodiment, X₁ is —C(H)═ or —C(R¹)═ and R¹ ischloro or lower alkyl. In one embodiment, X₁ is —C(H)═ or —C(R¹)═ and R¹is chloro or C₁₋₃ alkyl. In one embodiment, X₁ is —C(H)═ or —C(R¹)═ andR¹ is chloro or methyl.

In some embodiments of compounds of Formula I, further to any of theabove embodiments of Formula I, Cy₁ is cycloalkyl optionally substitutedwith one or more R⁴, phenyl optionally substituted with one or more R⁵,or 5 or 6 membered heteroaryl optionally substituted on an availablecarbon atom with one or more R⁶ and optionally substituted on anavailable nitrogen atom with R⁷, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula I, further to any of theabove embodiments of Formula I, Cy₁ is cycloalkyl optionally substitutedwith one or more R⁴, phenyl optionally substituted with one or more R⁵,or 5 or 6 membered heteroaryl optionally substituted on an availablecarbon atom with one or more R⁶ and optionally substituted on anavailable nitrogen atom with R⁷, wherein cycloalkyl is cyclohexyl, orcycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In some embodiments of compounds of Formula I, further to any of theabove embodiments of Formula I, L₁ is —C(H₂)—. In some embodiments ofcompounds of Formula I, further to any of the above embodiments ofFormula I, L₁ is —C(O)—.

In some embodiments of compounds of Formula I, further to any of theabove embodiments of Formula I, Y₁ is —N═ and R³ is hydrogen. In someembodiments of compounds of Formula I, further to any of the aboveembodiments of Formula I, Y₁ is —C(H)═ and R³ is fluoro.

In some embodiments (A) of compounds of Formula I, X₁ is N and all theother variables are as defined herein. Within embodiments (A), incertain instances, L₁ is CH₂, Y₁ is CH and R³ is F. In other instances,L₁ is CH₂, Y₁ is N and R³ is F. In yet other instances, L₁ is —C(═O)—,Y₁ is CH and R³ is F. In still other instances, L₁ is —C(═O)—, Y₁ is Nand R³ is F.

In some embodiments (B) of compounds of Formula I, X₁ is —C(R¹)═, R¹ andall the other variables are as defined herein. Within embodiments (B),in certain instances, L₁ is CH₂, Y₁ is CH and R³ is F. In otherinstances L₁ is —C(═O)—, Y₁ is CH and R³ is F. In yet other instances,L₁ is —CH₂—, Y₁ is N and R³ is F. In still other instances, L₁ is—C(═O)—, Y₁ is N and R³ is F.

In some embodiments (C) of compounds of Formula I, X₁ is N, R² is—N(R^(9a))(R^(9b)), and all the other variables are as defined herein.

In some embodiments of compounds of Formula I, Cy₁ is cycloalkyloptionally substituted with one or more R⁴. In certain instances, Cy₁ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, each ofwhich is optionally substituted with from 1 to 3 R⁴. All the othervariables are as defined herein.

In some embodiments of compounds of Formula I, Cy₁ is phenyl optionallysubstituted with one or more R⁵ and all the other variables are asdefined herein.

In some embodiments of compounds of Formula I, wherein Cy₁ is 5 or6-membered heteroaryl optionally substituted on an available carbon atomwith one or more R⁶ and optionally substituted on an available nitrogenatom with R⁷. In certain instances, Cy₁ is 3-pyridyl, 2-pyrrolyl,3-pyrrolyl or 4-pyrazolyl, optionally substituted on an available carbonatom with from 1 to 3 R⁶ and optionally substituted on an availablenitrogen atom with R⁷. In some embodiments, each R⁶ is independentlyselected from the group consisting of fluoro, chloro, bromo, cycloalkyl,lower alkyl optionally substituted with from one to three fluoro, andlower alkoxy optionally substituted with one to three fluoro; or two R⁶bound to adjacent carbon atoms of the heteroaryl ring form a fusedcycloalkyl ring. All the other variables are as defined herein.

In some embodiments of compounds of Formula I, R^(9a) is H and R^(9b) isselected from H, lower alkyl, lower alkyl substituted with hydroxy,lower alkyl substituted with lower alkoxy, lower alkyl substituted with1 to 3 fluoro groups, cycloalkyl optionally substituted with lower alkylor one to three fluoro, cycloalkylalkyl optionally substituted withlower alkyl or one to three fluoro substituents, heterocycloalkyloptionally substituted with lower alkyl, heterocycloalkylalkyl,arylalkyl optionally substituted with from 1 to 3 members selected fromlower alkyl, fluoro or haloalkyl and heteroarylalkyl optionallysubstituted with from one to three members selected from alkyl, fluoroor haloalkyl. In certain instances, R^(9a) is H and R^(9b) is selectedfrom (i) H, methyl, ethyl, t-butyl, propyl, isopropyl, 2-butyl, n-butyl,2-hydroxy-2-methylpropyl, 2-methoxyethyl, 3-methoxypropyl,2,2,2-trifluoroethyl, or 4-methoxybutyl and (ii) cyclopropyl,cyclobutyl, cyclopentyl, cylohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexymethyl, benzyl, 1-methylbenzyl,4,4-difluorocyclohexyl, 2-tetrahydrofuranylmethyl, 4-piperadinyl,3-pyridyl, 2-pyridyl or 4-pyridyl, each of which is optionallysubstituted with from 1 to 3 members selected from lower alkyl, loweralkoxy, fluoro or CF₃. All the other variables are as defined herein.

In some embodiments of compounds of Formula I, —N(R^(9a))(R^(9b)) is1-piperadinyl, 4-morpholinyl, 1-piperazinyl or 1-pyrrolidinyl, each ofwhich is optionally substituted with one to three members selected fromlower alkyl, haloalkyl, lower alkoxy or fluoro. All the other variablesare as defined herein.

In a second aspect, compounds of Formula I having the structureaccording to the following Formula Ia are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₂ is —N═ and R¹⁵ is hydrogen; or Y₂ is —C(H)═ and R¹⁵ is fluoro        or chloro;    -   L₂ is —C(H₂)— or —C(O)—;    -   Cy₂ is cycloalkyl optionally substituted with one or more R¹⁶,        phenyl optionally substituted with one or more R¹⁷, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R¹⁸ and optionally substituted on        an available nitrogen atom with R¹⁹;    -   R¹⁴ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R²⁰,        —N(R^(9a))(R^(9b)), and —O—R²¹;    -   each R¹⁶ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R¹⁷ is independently selected from the group consisting of        fluoro, chloro, —O—R²², —S—R²³, —S(O₂)—R²⁴, and lower alkyl        optionally substituted with one or more R²⁵;    -   each R¹⁸ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R¹⁸ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R¹⁹ is cycloalkyl, lower alkoxy, or lower alkyl optionally        substituted with one or more fluoro;    -   R²⁰ is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R²¹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R²², R²³ and R²⁴ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R²⁵ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ia, R¹⁴ is selected from thegroup consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁴ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, R¹⁴ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ia, further to any of theabove embodiments of Formula Ia, Cy₂ is cycloalkyl optionallysubstituted with one or more R¹⁶, phenyl optionally substituted with oneor more R¹⁷, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R¹⁸ and optionally substituted onan available nitrogen atom with R¹⁹, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ia, further to any of theabove embodiments of Formula Ia, Cy₂ is cycloalkyl optionallysubstituted with one or more R¹⁶, phenyl optionally substituted with oneor more R¹⁷, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R¹⁸ and optionally substituted onan available nitrogen atom with R¹⁹, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In some embodiments of compounds of Formula Ia, further to any of theabove embodiments of Formula Ia, L₂ is —C(H₂)—. In some embodiments ofcompounds of Formula Ia, further to any of the above embodiments ofFormula Ia, L₂ is —C(O)—.

In some embodiments of compounds of Formula Ia, further to any of theabove embodiments of Formula Ia, Y₂ is —N═ and R¹⁵ is hydrogen. In someembodiments of compounds of Formula Ia, further to any of the aboveembodiments of Formula Ia, Y₂ is —C(H)═ and R¹⁵ is fluoro.

In a third aspect, compounds of Formula I having the structure accordingto the following Formula Ib are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₃ is cycloalkyl optionally substituted with one or more R²⁷,        phenyl optionally substituted with one or more R²⁸, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R²⁹ and optionally substituted on        an available nitrogen atom with R³⁰;    -   R²⁶ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R³¹, and —O—R³²;    -   each R²⁷ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R²⁸ is independently selected from the group consisting of        fluoro, chloro, —O—R³³, —S—R³⁴, —S(O₂)—R³⁵, and lower alkyl        optionally substituted with one or more R³⁶;    -   each R²⁹ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R²⁹ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R³⁰ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   R³¹ is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R³² is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R³³, R³⁴ and R³⁵ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R³⁶ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ib, R²⁶ is selected from thegroup consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁶ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, R²⁶ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ib, further to any of theabove embodiments of Formula Ib, Cy₃ is cycloalkyl optionallysubstituted with one or more R²⁷, phenyl optionally substituted with oneor more R²⁸, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R²⁹ and optionally substituted onan available nitrogen atom with R³⁰, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ib, further to any of theabove embodiments of Formula Ib, Cy₃ is cycloalkyl optionallysubstituted with one or more R²⁷, phenyl optionally substituted with oneor more R²⁸, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R²⁹ and optionally substituted onan available nitrogen atom with R³⁰, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a fourth aspect, compounds of Formula I having the structureaccording to the following Formula Ic are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₄ is cycloalkyl optionally substituted with one or more R³⁸,        phenyl optionally substituted with one or more R³⁹, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁴⁰ and optionally substituted on        an available nitrogen atom with R⁴¹;    -   R³⁷ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R⁴², and —O—R⁴³;    -   each R³⁸ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R³⁹ is independently selected from the group consisting of        fluoro, chloro, —O—R⁴⁴, —S—R⁴⁵, —S(O₂)—R⁴⁶, and lower alkyl        optionally substituted with one or more R⁴⁷;    -   each R⁴⁰ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁴⁰ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁴¹ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   R⁴² is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R⁴³ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R⁴⁴, R⁴⁵ and R⁴⁶ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁴⁷ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ic, R³⁷ is selected from thegroup consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R³⁷ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, R³⁷ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ic, further to any of theabove embodiments of Formula Ic, Cy₄ is cycloalkyl optionallysubstituted with one or more R³⁸, phenyl optionally substituted with oneor more R³⁹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁴⁰ and optionally substituted onan available nitrogen atom with R⁴¹, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ic, further to any of theabove embodiments of Formula Ic, Cy₄ is cycloalkyl optionallysubstituted with one or more R³⁸, phenyl optionally substituted with oneor more R³⁹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁴⁰ and optionally substituted onan available nitrogen atom with R⁴¹, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a fifth aspect, compounds of Formula I having the structure accordingto the following Formula Id are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₅ is cycloalkyl optionally substituted with one or more R⁴⁹,        phenyl optionally substituted with one or more R⁵⁰, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁵¹ and optionally substituted on        an available nitrogen atom with R⁵²;    -   R⁴⁸ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R⁵³, and —O—R⁵⁴;    -   each R⁴⁹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁵⁰ is independently selected from the group consisting of        fluoro, chloro, —O—R⁵⁵, —S—R⁵⁶, —S(O₂)—R⁵⁷, and lower alkyl        optionally substituted with one or more R⁵⁸;    -   each R⁵¹ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁵¹ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁵² is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   R⁵³ is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R⁵⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R⁵⁵, R⁵⁶ and R⁵⁷ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁵⁸ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Id, R⁴⁸ is selected from thegroup consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R⁴⁸ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, R⁴⁸ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Id, further to any of theabove embodiments of Formula Id, Cy₅ is cycloalkyl optionallysubstituted with one or more R⁴⁹, phenyl optionally substituted with oneor more R⁵⁰, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁵¹ and optionally substituted onan available nitrogen atom with R⁵², wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Id, further to any of theabove embodiments of Formula Id, Cy₅ is cycloalkyl optionallysubstituted with one or more R⁴⁹, phenyl optionally substituted with oneor more R⁵⁰, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁵¹ and optionally substituted onan available nitrogen atom with R⁵², wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a sixth aspect, compounds of Formula I having the structure accordingto the following Formula Ie are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₆ is cycloalkyl optionally substituted with one or more R⁶⁰,        phenyl optionally substituted with one or more R⁶¹, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁶² and optionally substituted on        an available nitrogen atom with R⁶³;    -   R⁵⁹ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R⁶⁴, and —O—R⁶⁵;    -   each R⁶⁰ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁶¹ is independently selected from the group consisting of        fluoro, chloro, —O—R⁶⁶, —S—R⁶⁷, —S(O₂)—R⁶⁸, and lower alkyl        optionally substituted with one or more R⁶⁹;    -   each R⁶² is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁶² bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁶³ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   R⁶⁴ is fluoro or lower alkoxy optionally substituted with one or        more fluoro;    -   R⁶⁵ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   each R⁶⁶, R⁶⁷ and R⁶⁸ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁶⁹ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ie, R⁵⁹ is selected from thegroup consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R⁵⁹ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, R⁵⁹ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ie, further to any of theabove embodiments of Formula Ie, Cy₆ is cycloalkyl optionallysubstituted with one or more R⁶⁰, phenyl optionally substituted with oneor more R⁶¹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁶² and optionally substituted onan available nitrogen atom with R⁶³, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ie, further to any of theabove embodiments of Formula Ie, Cy₆ is cycloalkyl optionallysubstituted with one or more R⁶⁰, phenyl optionally substituted with oneor more R⁶¹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁶² and optionally substituted onan available nitrogen atom with R⁶³, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a seventh aspect, compounds of Formula I having the structureaccording to the following Formula If are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₃ is —N═ and R⁷¹ is hydrogen; or Y₃ is —C(H)═ and R⁷¹ is        fluoro;    -   L₃ is —C(H₂)— or —C(O)—;    -   Cy₇ is cycloalkyl optionally substituted with one or more R⁷²,        phenyl optionally substituted with one or more R⁷³, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁷⁴ and optionally substituted on        an available nitrogen atom with R⁷⁵;    -   R⁷⁰ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   each R⁷² is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁷³ is independently selected from the group consisting of        fluoro, chloro, —O—R⁷⁶, —S—R⁷⁷, —S(O₂)—R⁷⁸, and lower alkyl        optionally substituted with one or more R⁷⁹;    -   each R⁷⁴ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁷⁴ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁷⁵ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   each R⁷⁶, R⁷⁷ and R⁷⁸ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁷⁹ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula If, R⁷⁰ is hydrogen, chloroor lower alkyl. In one embodiment, R⁷⁰ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R⁷⁰ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula If, further to any of theabove embodiments of Formula If, Cy₇ is cycloalkyl optionallysubstituted with one or more R⁷², phenyl optionally substituted with oneor more R⁷³, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁷⁴ and optionally substituted onan available nitrogen atom with R⁷⁵, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula If, further to any of theabove embodiments of Formula If, Cy₇ is cycloalkyl optionallysubstituted with one or more R⁷², phenyl optionally substituted with oneor more R⁷³, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁷⁴ and optionally substituted onan available nitrogen atom with R⁷⁵, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In some embodiments of compounds of Formula If, further to any of theabove embodiments of Formula If, L₃ is —C(H₂)—. In some embodiments ofcompounds of Formula If, further to any of the above embodiments ofFormula If, L₃ is —C(O)—.

In some embodiments of compounds of Formula If, further to any of theabove embodiments of Formula If, Y₃ is —N═ and R⁷¹ is hydrogen. In someembodiments of compounds of Formula If, further to any of the aboveembodiments of Formula If, Y₃ is —C(H)═ and R⁷¹ is fluoro.

In an eighth aspect, compounds of Formula I having the structureaccording to the following Formula Ig are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₈ is cycloalkyl optionally substituted with one or more R⁸¹,        phenyl optionally substituted with one or more R⁸², or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁸³ and optionally substituted on        an available nitrogen atom with R⁸⁴;    -   R⁸⁰ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   each R⁸¹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁸² is independently selected from the group consisting of        fluoro, chloro, —O—R⁸⁵, —S(O₂)—R⁸⁷, and lower alkyl optionally        substituted with one or more R⁸⁸;    -   each R⁸³ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁸³ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁸⁴ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   each R⁸⁵, R⁸⁶ and R⁸⁷ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁸⁸ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ig, R⁸⁰ is hydrogen, chloroor lower alkyl. In one embodiment, R⁸⁰ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R⁸⁰ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ig, further to any of theabove embodiments of Formula Ig, Cy₈ is cycloalkyl optionallysubstituted with one or more R⁸¹, phenyl optionally substituted with oneor more R⁸², or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁸³ and optionally substituted onan available nitrogen atom with R⁸⁴, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ig, further to any of theabove embodiments of Formula Ig, Cy₈ is cycloalkyl optionallysubstituted with one or more R⁸¹, phenyl optionally substituted with oneor more R⁸², or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁸³ and optionally substituted onan available nitrogen atom with R⁸⁴, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a ninth aspect, compounds of Formula I having the structure accordingto the following Formula Ih are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₉ is cycloalkyl optionally substituted with one or more R⁹⁰,        phenyl optionally substituted with one or more R⁹¹, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R⁹² and optionally substituted on        an available nitrogen atom with R⁹³;    -   R⁸⁹ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   each R⁹⁰ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R⁹¹ is independently selected from the group consisting of        fluoro, chloro, —O—R⁹⁴, —S—R⁹⁵, —S(O₂)—R⁹⁶, and lower alkyl        optionally substituted with one or more R⁹⁷;    -   each R⁹² is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R⁹² bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R⁹³ is cycloalkyl or lower alkyl optionally substituted with one        or more fluoro;    -   each R⁹⁴, R⁹⁵ and R⁹⁶ are independently lower alkyl optionally        substituted with one or more fluoro; and    -   each R⁹⁷ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ih, R⁸⁹ is hydrogen, chloroor lower alkyl. In one embodiment, R⁸⁹ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R⁸⁹ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ih, further to any of theabove embodiments of Formula Ih, Cy₉ is cycloalkyl optionallysubstituted with one or more R⁹⁰, phenyl optionally substituted with oneor more R⁹¹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁹² and optionally substituted onan available nitrogen atom with R⁹³, wherein cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and heteroaryl ispyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ih, further to any of theabove embodiments of Formula Ih, Cy₉ is cycloalkyl optionallysubstituted with one or more R⁹⁰, phenyl optionally substituted with oneor more R⁹¹, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R⁹² and optionally substituted onan available nitrogen atom with R⁹³, wherein cycloalkyl is cyclohexyl,or cycloheptyl, and heteroaryl is pyridin-3-yl or pyrazol-4-yl.

In a tenth aspect, compounds of Formula I having the structure accordingto the following Formula Ii are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₀ is cycloalkyl optionally substituted with one or more R⁹⁹,        phenyl optionally substituted with one or more R¹⁰⁰, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R¹⁰¹ and optionally substituted on        an available nitrogen atom with R¹⁰²;    -   R⁹⁸ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   each R⁹⁹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R¹⁰⁰ is independently selected from the group consisting of        fluoro, chloro, —O—R¹⁰³, —S—R¹⁰⁴, —S(O₂)—R¹⁰⁵, and lower alkyl        optionally substituted with one or more R¹⁰⁶;    -   each R¹⁰¹ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R¹⁰¹ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R¹⁰² is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   each R¹⁰², R¹⁰⁴ and R¹⁰⁵ are independently lower alkyl        optionally substituted with one or more fluoro; and    -   each R¹⁰⁶ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ii, R⁹⁸ is hydrogen, chloroor lower alkyl. In one embodiment, R⁹⁸ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R⁹⁸ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ii, further to any of theabove embodiments of Formula Ii, Cy₁₀ is cycloalkyl optionallysubstituted with one or more R⁹⁹, phenyl optionally substituted with oneor more R¹⁰⁰, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R¹⁰¹ and optionally substitutedon an available nitrogen atom with R¹⁰², wherein cycloalkyl iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, andheteroaryl is pyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ii, further to any of theabove embodiments of Formula Ii, Cy₁₀ is cycloalkyl optionallysubstituted with one or more R⁹⁹, phenyl optionally substituted with oneor more R¹⁰⁰, or 5 or 6 membered heteroaryl optionally substituted on anavailable carbon atom with one or more R¹⁰¹ and optionally substitutedon an available nitrogen atom with R¹⁰², wherein cycloalkyl iscyclohexyl, or cycloheptyl, and heteroaryl is pyridin-3-yl orpyrazol-4-yl.

In an eleventh aspect, compounds of Formula I having the structureaccording to the following Formula Ij are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₁ is cycloalkyl optionally substituted with one or more R¹⁰⁸,        phenyl optionally substituted with one or more R¹⁰⁹, or 5 or 6        membered heteroaryl optionally substituted on an available        carbon atom with one or more R¹¹⁰ and optionally substituted on        an available nitrogen atom with R¹¹¹;    -   R¹⁰⁷ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   each R¹⁰⁸ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   each R¹⁰⁹ is independently selected from the group consisting of        fluoro, chloro, —O—R¹¹², —S—R¹¹³, —S(O₂)—R¹¹⁴, and lower alkyl        optionally substituted with one or more R¹¹⁵;    -   each R¹¹⁰ is independently selected from the group consisting of        fluoro, chloro, bromo, cycloalkyl, lower alkyl optionally        substituted with one or more fluoro, and lower alkoxy optionally        substituted with one or more fluoro; or two R¹¹⁰ bound to        adjacent carbon atoms of the heteroaryl ring, taken together,        form a fused cycloalkyl ring;    -   R¹¹¹ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   each R¹¹², R¹¹³ and R¹¹⁴ are independently lower alkyl        optionally substituted with one or more fluoro; and    -   each R¹¹⁵ is independently selected from the group consisting of        fluoro, —OH, and lower alkoxy optionally substituted with one or        more fluoro.

In some embodiments of compounds of Formula Ij, R¹⁰⁷ is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁰⁷ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁰⁷ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ij, further to any of theabove embodiments of Formula Ij, Cy₁₁ is cycloalkyl optionallysubstituted with one or more R¹⁰⁸, phenyl optionally substituted withone or more R¹⁰⁹, or 5 or 6 membered heteroaryl optionally substitutedon an available carbon atom with one or more R¹¹⁰ and optionallysubstituted on an available nitrogen atom with R¹¹¹, wherein cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, andheteroaryl is pyridinyl or pyrazolyl.

In some embodiments of compounds of Formula Ij, further to any of theabove embodiments of Formula Ij, Cy₁₁ is cycloalkyl optionallysubstituted with one or more R¹⁰⁸, phenyl optionally substituted withone or more R¹⁰⁹, or 5 or 6 membered heteroaryl optionally substitutedon an available carbon atom with one or more R¹¹⁰ and optionallysubstituted on an available nitrogen atom with R¹¹¹, wherein cycloalkylis cyclohexyl, or cycloheptyl, and heteroaryl is pyridin-3-yl orpyrazol-4-yl.

In a twelfth aspect, compounds of Formula I having the structureaccording to the following Formula Ik are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   X₂ is —N═, —C(H)═, or —C(R¹¹⁶)═;    -   Y₄ is —N═ and R¹¹⁸ is hydrogen; or Y₄ is —C(H)═ and R¹¹⁸ is        fluoro;    -   L₄ is —C(H₂)— or —C(O)—;    -   Cy₁₂ is cycloalkyl optionally substituted with one or more R¹¹⁹;    -   when X₂ is —C(R¹¹⁶)═, R¹¹⁷ is hydrogen;    -   when X₂ is —N═ or —C(H)═, R¹¹⁷ is selected from the group        consisting of hydrogen, cycloalkyl, lower alkyl optionally        substituted with one or more R¹²⁰, and —O—R¹²¹;    -   R¹¹⁶ is fluoro, chloro, or lower alkyl optionally substituted        with one or more fluoro;    -   each R¹¹⁹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹²⁰ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹²¹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ik, X₂ is —N═ and R¹¹⁷ isselected from the group consisting of hydrogen, cycloalkyl, lower alkyloptionally substituted with one or more R¹²⁰, and —O—R¹²¹. In oneembodiment, X₂ is —N═ and R¹¹⁷ is selected from the group consisting ofcycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted withlower alkoxy. In one embodiment, X₂ is —N═ and R¹¹⁷ is selected from thegroup consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, X₂ is —N═ andR¹¹⁷ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ik, X₂ is —C(H)═ or—C(R¹¹⁶)═ and R¹¹⁶ is fluoro, chloro, or lower alkyl optionallysubstituted with one or more fluoro. In one embodiment, X₂ is —C(H)═ or—C(R¹¹⁶)═ and R¹¹⁶ is chloro or lower alkyl. In one embodiment, X₂ is—C(H)═ or —C(R¹¹⁶)═ and R¹¹⁶ is chloro or C₁₋₃ alkyl. In one embodiment,X₂ is —C(H)═ or —C(R¹¹⁶)═ and R¹¹⁶ is chloro or methyl.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Cy₁₂ is cyclopentyl optionallysubstituted with 1 or 2 R¹¹⁹, cyclohexyl optionally substituted with 1or 2 R¹¹⁹, or cycloheptyl optionally substituted with 1 or 2 R¹¹⁹.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Cy₁₂ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Cy₁₂ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Cy₁₂ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Cy₁₂ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, L₄ is —C(H₂)—. In some embodiments ofcompounds of Formula Ik, further to any of the above embodiments ofFormula Ik, L₄ is —C(O)—.

In some embodiments of compounds of Formula Ik, further to any of theabove embodiments of Formula Ik, Y₄ is —N═ and R¹¹⁸ is hydrogen. In someembodiments of compounds of Formula Ik, further to any of the aboveembodiments of Formula Ik, Y₄ is —C(H)═ and R¹¹⁸ is fluoro.

In a thirteenth aspect, compounds of Formula I having the structureaccording to the following Formula Im are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₅ is —N═ and R¹²³ is hydrogen; or Y₅ is —C(H)═ and R¹²³ is        fluoro;    -   L₅ is —C(H₂)— or —C(O)—;    -   Cy₁₃ is cycloalkyl optionally substituted with one or more R¹²⁴;    -   R¹²² is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R¹²⁵, and —O—R¹²⁶;    -   each R¹²⁴ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹²⁵ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹²⁶ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Im, R¹²² is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment R¹²² is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment R¹²² isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Cy₁₃ is cyclopentyl optionallysubstituted with 1 or 2 R¹²⁴, cyclohexyl optionally substituted with 1or 2 R¹²⁴, or cycloheptyl optionally substituted with 1 or 2 R¹²⁴.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Cy₁₃ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Cy₁₃ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Cy₁₃ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Cy₁₃ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, L₅ is —C(H₂)—. In some embodiments ofcompounds of Formula Im, further to any of the above embodiments ofFormula Im, L₅ is —C(O)—.

In some embodiments of compounds of Formula Im, further to any of theabove embodiments of Formula Im, Y₅ is —N═ and R¹²³ is hydrogen. In someembodiments of compounds of Formula Im, further to any of the aboveembodiments of Formula Im, Y₅ is —C(H)═ and R¹²³ is fluoro.

In a fourteenth aspect, compounds of Formula I having the structureaccording to the following Formula In are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₄ is cycloalkyl optionally substituted with one or more R¹²⁸;    -   R¹²⁷ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R¹²⁹, and —O—R¹³⁰;    -   each R¹²⁸ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹²⁹ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹³⁰ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula In, R¹²⁷ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment R¹²⁷ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment R¹²⁷ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula In, further to any of theabove embodiments of Formula In, Cy₁₄ is cyclopentyl optionallysubstituted with 1 or 2 R¹²⁸, cyclohexyl optionally substituted with 1or 2 R¹²⁸, or cycloheptyl optionally substituted with 1 or 2 R¹²⁸.

In some embodiments of compounds of Formula In, further to any of theabove embodiments of Formula In, Cy₁₄ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula In, further to any of theabove embodiments of Formula In, Cy₁₄ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula In, further to any of theabove embodiments of Formula In, Cy₁₄ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula In, further to any of theabove embodiments of Formula In, Cy₁₄ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a fifteenth aspect, compounds of Formula I having the structureaccording to the following Formula Io are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₅ is cycloalkyl optionally substituted with one or more R¹³²;    -   R¹³¹ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R¹³³, and —O—R¹³⁴;    -   each R¹³² is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹³³ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹³⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Io, R¹³¹ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment R¹³¹ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment R¹³¹ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Io, further to any of theabove embodiments of Formula Io, Cy₁₅ is cyclopentyl optionallysubstituted with 1 or 2 R¹³², cyclohexyl optionally substituted with 1or 2 R¹³², or cycloheptyl optionally substituted with 1 or 2 R¹³².

In some embodiments of compounds of Formula Io, further to any of theabove embodiments of Formula Io, Cy₁₅ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Io, further to any of theabove embodiments of Formula Io, Cy₁₅ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Io, further to any of theabove embodiments of Formula Io, Cy₁₅ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Io, further to any of theabove embodiments of Formula Io, Cy₁₅ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a sixteenth aspect, compounds of Formula I having the structureaccording to the following Formula Ip are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₆ is cycloalkyl optionally substituted with one or more R¹³⁶;    -   R¹³⁵ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R¹³⁷, and —O—R¹³⁸;    -   each R¹³⁶ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹³⁷ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹³⁸ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ip, R¹³⁵ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment R¹³⁵ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment R¹³⁵ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ip, further to any of theabove embodiments of Formula Ip, Cy₁₆ is cyclopentyl optionallysubstituted with 1 or 2 R¹³⁶, cyclohexyl optionally substituted with 1or 2 R¹³⁶, or cycloheptyl optionally substituted with 1 or 2 R¹³⁶.

In some embodiments of compounds of Formula Ip, further to any of theabove embodiments of Formula Ip, Cy₁₆ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ip, further to any of theabove embodiments of Formula Ip, Cy₁₆ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ip, further to any of theabove embodiments of Formula Ip, Cy₁₆ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ip, further to any of theabove embodiments of Formula Ip, Cy₁₆ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a seventeenth aspect, compounds of Formula I having the structureaccording to the following Formula Iq are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₆ is cycloalkyl optionally substituted with one or more R¹⁴⁰;    -   R¹³⁹ is selected from the group consisting of cycloalkyl, lower        alkyl optionally substituted with one or more R¹⁴¹, and —O—R¹⁴²;    -   each R¹⁴⁰ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro;    -   R¹⁴¹ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁴² is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iq, R¹³⁹ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment R¹³⁹ is selectedfrom the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy,and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment R¹³⁹ isselected from the group consisting of methyl, cyclopropyl, methoxy,ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iq, further to any of theabove embodiments of Formula Iq, Cy₁₇ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁴⁰, cyclohexyl optionally substituted with 1or 2 R¹⁴⁰, or cycloheptyl optionally substituted with 1 or 2 R¹⁴⁰.

In some embodiments of compounds of Formula Iq, further to any of theabove embodiments of Formula Iq, Cy₁₇ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iq, further to any of theabove embodiments of Formula Iq, Cy₁₇ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iq, further to any of theabove embodiments of Formula Iq, Cy₁₇ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iq, further to any of theabove embodiments of Formula Iq, Cy₁₇ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In an eighteenth aspect, compounds of Formula I having the structureaccording to the following Formula Ir are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₆ is —N═ and R¹⁴⁴ is hydrogen; or Y₆ is —C(H)═ and R¹⁴⁴ is        fluoro;    -   L₆ is —C(H₂)— or —C(O)—;    -   Cy₁₈ is cycloalkyl optionally substituted with one or more R¹⁴⁵;    -   R¹⁴³ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹⁴⁵ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro.

In some embodiments of compounds of Formula Ir, R¹⁴³ is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁴³ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁴³ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Cy₁₈ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁴⁵, cyclohexyl optionally substituted with 1or 2 R¹⁴⁵, or cycloheptyl optionally substituted with 1 or 2 R¹⁴⁵.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Cy₁₈ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Cy₁₈ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Cy₁₈ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Cy₁₈ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, L₆ is —C(H₂)—. In some embodiments ofcompounds of Formula Ir, further to any of the above embodiments ofFormula Ir, L₆ is —C(O)—.

In some embodiments of compounds of Formula Ir, further to any of theabove embodiments of Formula Ir, Y₆ is —N═ and R¹⁴⁴ is hydrogen. In someembodiments of compounds of Formula Ir, further to any of the aboveembodiments of Formula Ir, Y₆ is —C(H)═ and R¹⁴⁴ is fluoro.

In a nineteenth aspect, compounds of Formula I having the structureaccording to the following Formula Is are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₁₉ is cycloalkyl optionally substituted with one or more R¹⁴⁷;    -   R¹⁴⁶ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹⁴⁷ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro.

In some embodiments of compounds of Formula Is, R¹⁴⁶ is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁴⁶ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁴⁶ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Is, further to any of theabove embodiments of Formula Is, Cy₁₉ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁴⁷, cyclohexyl optionally substituted with 1or 2 R¹⁴⁷, or cycloheptyl optionally substituted with 1 or 2 R¹⁴⁷.

In some embodiments of compounds of Formula Is, further to any of theabove embodiments of Formula Is, Cy₁₉ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Is, further to any of theabove embodiments of Formula Is, Cy₁₉ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Is, further to any of theabove embodiments of Formula Is, Cy₁₉ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Is, further to any of theabove embodiments of Formula Is, Cy₁₉ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a twentieth aspect, compounds of Formula I having the structureaccording to the following Formula It are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₂₀ is cycloalkyl optionally substituted with one or more R¹⁴⁹;    -   R¹⁴⁸ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹⁴⁹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro.

In some embodiments of compounds of Formula It, R¹⁴⁸ is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁴⁸ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁴⁸ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula It, further to any of theabove embodiments of Formula It, Cy₂₀ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁴⁹, cyclohexyl optionally substituted with 1or 2 R¹⁴⁹, or cycloheptyl optionally substituted with 1 or 2 R¹⁴⁹.

In some embodiments of compounds of Formula It, further to any of theabove embodiments of Formula It, Cy₂₀ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula It, further to any of theabove embodiments of Formula It, Cy₂₀ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula It, further to any of theabove embodiments of Formula It, Cy₂₀ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula It, further to any of theabove embodiments of Formula It, Cy₂₀ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a twenty-first aspect, compounds of Formula I having the structureaccording to the following Formula Iu are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₂₁ is cycloalkyl optionally substituted with one or more R¹⁵¹;    -   R¹⁵⁰ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹⁵¹ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro.

In some embodiments of compounds of Formula Iu, R¹⁵⁰ is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁵⁰ is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁵⁰ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Iu, further to any of theabove embodiments of Formula Iu, Cy₂₁ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁵¹, cyclohexyl optionally substituted with 1or 2 R¹⁵¹, or cycloheptyl optionally substituted with 1 or 2 R¹⁵¹.

In some embodiments of compounds of Formula Iu, further to any of theabove embodiments of Formula Iu, Cy₂₁ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iu, further to any of theabove embodiments of Formula Iu, Cy₂₁ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iu, further to any of theabove embodiments of Formula Iu, Cy₂₁ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iu, further to any of theabove embodiments of Formula Iu, Cy₂₁ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a twenty-second aspect, compounds of Formula I having the structureaccording to the following Formula Iv are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Cy₂₂ is cycloalkyl optionally substituted with one or more R¹⁵³;    -   R¹⁵² is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   each R¹⁵³ is independently selected from the group consisting of        fluoro, —OH, lower alkyl optionally substituted with one or more        fluoro, and lower alkoxy optionally substituted with one or more        fluoro.

In some embodiments of compounds of Formula Iv, R¹⁵² is hydrogen, chloroor lower alkyl. In one embodiment, R¹⁵² is hydrogen, chloro or C₁₋₃alkyl. In one embodiment, R¹⁵² is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Iv, further to any of theabove embodiments of Formula Iv, Cy₂₂ is cyclopentyl optionallysubstituted with 1 or 2 R¹⁵³, cyclohexyl optionally substituted with 1or 2 R¹⁵³, or cycloheptyl optionally substituted with 1 or 2 R¹⁵³.

In some embodiments of compounds of Formula Iv, further to any of theabove embodiments of Formula Iv, Cy₂₂ is cyclopentyl optionallysubstituted with 1 or 2 fluoro, or for 2 lower alkyl, or 1 or 2 —OH, or1 or 2 lower alkoxy; cyclohexyl optionally substituted with 1 or 2fluoro, or 1 or 2 lower alkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy; orcycloheptyl optionally substituted with 1 or 2 fluoro, or 1 or 2 loweralkyl, or 1 or 2 —OH, or 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iv, further to any of theabove embodiments of Formula Iv, Cy₂₂ is cyclopentyl, cyclopentylsubstituted with 1 or 2 fluoro, cyclopentyl substituted with 1 or 2lower alkyl, cyclopentyl substituted with 1 or 2 —OH, or cyclopentylsubstituted with 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iv, further to any of theabove embodiments of Formula Iv, Cy₂₂ is cyclohexyl, cyclohexylsubstituted with 1 or 2 fluoro, cyclohexyl substituted with 1 or 2 loweralkyl, cyclohexyl substituted with 1 or 2 —OH, or cyclohexyl substitutedwith 1 or 2 lower alkoxy.

In some embodiments of compounds of Formula Iv, further to any of theabove embodiments of Formula Iv, Cy₂₂ is cycloheptyl, cycloheptylsubstituted with 1 or 2 fluoro, cycloheptyl substituted with 1 or 2lower alkyl, cycloheptyl substituted with 1 or 2 —OH, or cycloheptylsubstituted with 1 or 2 lower alkoxy.

In a twenty-third aspect, compounds of Formula I having the structureaccording to the following Formula Iw are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   X₃ is —N═, —C(H)═, or —C(R¹⁵⁴)═;    -   Y₇ is —N═ and R¹⁵⁶ is hydrogen; or Y₇ is —C(H)═ and R¹⁵⁶ is        fluoro;    -   L₇ is —C(H₂)— or —C(O)—;    -   when X₃ is —C(R¹⁵⁴)═, R¹⁵⁵ is hydrogen;    -   when X₃ is —N═ or —C(H)═, R¹⁵⁵ is selected from the group        consisting of hydrogen, cycloalkyl, lower alkyl optionally        substituted with one or more R¹⁵⁸, and —O—R¹⁵⁹;    -   R¹⁵⁴ is fluoro, chloro, or lower alkyl optionally substituted        with one or more fluoro;    -   R¹⁵⁷ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁵⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁵⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iw, X₃ is —N═ and R¹⁵⁵ isselected from the group consisting of hydrogen, cycloalkyl, lower alkyloptionally substituted with one or more R¹⁵⁸, and —O—R¹⁵⁹. In oneembodiment, X₃ is —N═ and R¹⁵⁵ is selected from the group consisting ofcycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted withlower alkoxy. In one embodiment, X₃ is —N═ and R¹⁵⁵ is selected from thegroup consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, X₃ is —N═ andR¹⁵⁵ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iw, X₃ is —C(H)═ or—C(R¹⁵⁴)═ and R¹⁵⁴ is fluoro, chloro, or lower alkyl optionallysubstituted with one or more fluoro. In one embodiment, X₃ is —C(H)═ or—C(R¹⁵⁴)═ and R¹⁵⁴ is chloro or lower alkyl. In one embodiment, X₃ is—C(H)═ or —C(R¹⁵⁴)═ and R¹⁵⁴ is chloro or C₁₋₃ alkyl. In one embodiment,X₃ is —C(H)═ or —C(R¹⁵⁴)— and R¹⁵⁴ is chloro or methyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is C₃₋₆ cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is lower alkyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, R¹⁵⁷ is ethyl.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, L₇ is —C(H₂)—. In some embodiments ofcompounds of Formula Iw, further to any of the above embodiments ofFormula Iw, L₇ is —C(O)—.

In some embodiments of compounds of Formula Iw, further to any of theabove embodiments of Formula Iw, Y₇ is —N═ and R¹⁵⁶ is hydrogen. In someembodiments of compounds of Formula Iw, further to any of the aboveembodiments of Formula Iw, Y₇ is —C(H)═ and R¹⁵⁶ is fluoro.

In a twenty-fourth aspect, compounds of Formula I having the structureaccording to the following Formula Ix are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₈ is —N═ and R¹⁶¹ is hydrogen; or Y₈ is —C(H)═ and R¹⁶¹ is        fluoro;    -   L₈ is —C(H₂)— or —C(O)—;    -   R¹⁶⁰ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R¹⁶³, and —O—R¹⁶⁴;    -   R¹⁶² is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁶³ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁶⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ix, R¹⁶⁰ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁶⁰ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁶⁰ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is C₃₋₆ cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is lower alkyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, R¹⁶² is ethyl.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, L₈ is —C(H₂)—. In some embodiments ofcompounds of Formula Ix, further to any of the above embodiments ofFormula Ix, L₈ is —C(O)—.

In some embodiments of compounds of Formula Ix, further to any of theabove embodiments of Formula Ix, Y₈ is —N═ and R¹⁶¹ is hydrogen. In someembodiments of compounds of Formula Ix, further to any of the aboveembodiments of Formula Ix, Y₈ is —C(H)═ and R¹⁶¹ is fluoro.

In a twenty-fifth aspect, compounds of Formula I having the structureaccording to the following Formula Iy are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁶⁵ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R¹⁶⁷, and —O—R¹⁶⁸;    -   R¹⁶⁶ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁶⁷ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁶⁸ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iy, R¹⁶⁵ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁶⁵ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁶⁵ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is C₃₋₆ cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is lower alkyl.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Iy, further to any of theabove embodiments of Formula Iy, R¹⁶⁶ is ethyl.

In a twenty-sixth aspect, compounds of Formula I having the structureaccording to the following Formula Iz are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁶⁹ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R¹⁷¹, and —O—R¹⁷²;    -   R¹⁷⁰ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁷¹ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁷² is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iz, R¹⁶⁹ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁶⁹ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁶⁹ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is C₃₋₆ cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is lower alkyl.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Iz, further to any of theabove embodiments of Formula Iz, R¹⁷⁰ is ethyl.

In a twenty-seventh aspect, compounds of Formula I having the structureaccording to the following Formula Iaa are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁷³ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R¹⁷⁵, and —O—R¹⁷⁶;    -   R¹⁷⁴ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁷⁵ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁷⁶ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iaa, R¹⁷³ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁷³ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁷³ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is lower alkyl.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Iaa, further to any of theabove embodiments of Formula Iaa, R¹⁷⁴ is ethyl.

In a twenty-eighth aspect, compounds of Formula I having the structureaccording to the following Formula Ibb are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁷⁷ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R¹⁷⁹, and —O—R¹⁸⁰;    -   R¹⁷⁸ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro;    -   R¹⁷⁹ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁸⁰ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ibb, R¹⁷⁷ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁷⁷ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁷⁷ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is lower alkyl.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Ibb, further to any of theabove embodiments of Formula Ibb, R¹⁷⁸ is ethyl.

In a twenty-ninth aspect, compounds of Formula I having the structureaccording to the following Formula Icc are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₉ is —N═ and R¹⁸² is hydrogen; or Y₉ is —C(H)═ and R¹⁸² is        fluoro;    -   L₉ is —C(H₂)— or —C(O)—;    -   R¹⁸¹ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   R¹⁸³ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Icc, R¹⁸¹ is hydrogen,chloro or lower alkyl. In one embodiment, R¹⁸¹ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R¹⁸¹ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is lower alkyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, R¹⁸³ is ethyl.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, L₉ is —C(H₂)—. In some embodiments ofcompounds of Formula Icc, further to any of the above embodiments ofFormula Icc, L₉ is —C(O)—.

In some embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, Y₉ is —N═ and R¹⁸² is hydrogen. Insome embodiments of compounds of Formula Icc, further to any of theabove embodiments of Formula Icc, Y₉ is —C(H)═ and R¹⁸² is fluoro.

In a thirtieth aspect, compounds of Formula I having the structureaccording to the following Formula Idd are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁸⁴ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   R¹⁸⁵ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Idd, R¹⁸⁴ is hydrogen,chloro or lower alkyl. In one embodiment, R¹⁸⁴ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R¹⁸⁴ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is lower alkyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Idd, further to any of theabove embodiments of Formula Idd, R¹⁸⁵ is ethyl.

In a thirty-first aspect, compounds of Formula I having the structureaccording to the following Formula Tee are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁸⁶ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   R¹⁸⁷ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Tee, R¹⁸⁶ is hydrogen,chloro or lower alkyl. In one embodiment, R¹⁸⁶ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R¹⁸⁶ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is lower alkyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Tee, further to any of theabove embodiments of Formula Tee, R¹⁸⁷ is ethyl.

In a thirty-second aspect, compounds of Formula I having the structureaccording to the following Formula Iff are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁸⁸ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   R¹⁸⁹ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iff, R¹⁸⁸ is hydrogen,chloro or lower alkyl. In one embodiment, R¹⁸⁸ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R¹⁸⁸ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is lower alkyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Iff, further to any of theabove embodiments of Formula Iff, R¹⁸⁹ is ethyl.

In a thirty-third aspect, compounds of Formula I having the structureaccording to the following Formula Igg are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R¹⁹⁰ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro; and    -   R¹⁹¹ is cycloalkyl or lower alkyl optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Igg, R¹⁹⁰ is hydrogen,chloro or lower alkyl. In one embodiment, R¹⁹⁰ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R¹⁹⁰ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is cycloalkyl or lower alkyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is C₃₋₆ cycloalkyl or loweralkyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is cyclopropyl or lower alkyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is lower alkyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is C₁₋₃ alkyl.

In some embodiments of compounds of Formula Igg, further to any of theabove embodiments of Formula Igg, R¹⁹¹ is ethyl.

In a thirty-fourth aspect, compounds of Formula I having the structureaccording to the following Formula Ihh are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   X₄ is —N═, —C(H)═, or —C(R¹⁹²)═;    -   Y₁₀ is —N═ and R¹⁹⁴ is hydrogen; or Y₁₀ is —C(H)═ and R¹⁹⁴ is        fluoro;    -   L₁₀ is —C(H₂)— or —C(O)—;    -   when X₄ is —C(R¹⁹²)═, R¹⁹³ is hydrogen;    -   when X₄ is —N═ or —C(H)═, R¹⁹³ is selected from the group        consisting of hydrogen, cycloalkyl, lower alkyl optionally        substituted with one or more R¹⁹⁷, and —O—R¹⁹⁸;    -   R¹⁹² is fluoro, chloro, or lower alkyl optionally substituted        with one or more fluoro;    -   R¹⁹⁵ is hydrogen and R¹⁹⁶ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R¹⁹⁶ is hydrogen and R¹⁹⁵ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R¹⁹⁷ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R¹⁹⁸ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ihh, X₄ is —N═ and R¹⁹³ isselected from the group consisting of hydrogen, cycloalkyl, lower alkyloptionally substituted with one or more R¹⁹⁷, and —O—R¹⁹⁸. In oneembodiment, X₄ is —N═ and R¹⁹³ is selected from the group consisting ofcycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted withlower alkoxy. In one embodiment, X₄ is —N═ and R¹⁹³ is selected from thegroup consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, X₄ is —N═ andR¹⁹³ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ihh, X₄ is —C(H)═ or—C(R¹⁹²)═ and R¹⁹² is fluoro, chloro, or lower alkyl optionallysubstituted with one or more fluoro. In one embodiment, X₄ is —C(H)═ or—C(R¹⁹²)═ and R¹⁹² is chloro or lower alkyl. In one embodiment, X₄ is—C(H)═ or —C(R¹⁹²)═ and R¹⁹² is chloro or C₁₋₃ alkyl. In one embodiment,X₄ is —C(H)═ or —C(R¹⁹²)═ and R¹⁹² is chloro or methyl.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁶ is hydrogen and R¹⁹⁵ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁶ is hydrogen and R¹⁹⁵ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ihh, further to any of the aboveembodiments of Formula Ihh, R¹⁹⁶ is hydrogen and R¹⁹⁵ is lower alkyl. Insome embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁶ is hydrogen and R¹⁹⁵ is C₁₋₃alkyl. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁶ is hydrogen and R¹⁹⁵ ismethyl.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Ihh,further to any of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogenand R¹⁹⁶ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ iscycloalkyl. In some embodiments of compounds of Formula Ihh, further toany of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶is cyclopropyl.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ihh, further to any of the aboveembodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Ihh, further to any of the above embodiments ofFormula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ istrifluoromethyl. In some embodiments of compounds of Formula Ihh,further to any of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogenand R¹⁹⁶ is methyl. In some embodiments of compounds of Formula Ihh,further to any of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogenand R¹⁹⁶ is ethyl.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ihh, further to any of the aboveembodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is lower alkoxy.In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Ihh, further to anyof the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogen and R¹⁹⁶ ismethoxy or ethoxy. In some embodiments of compounds of Formula Ihh,further to any of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogenand R¹⁹⁶ is methoxy. In some embodiments of compounds of Formula Ihh,further to any of the above embodiments of Formula Ihh, R¹⁹⁵ is hydrogenand R¹⁹⁶ is ethoxy.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, L₁₀ is —C(H₂)—. In some embodiments ofcompounds of Formula Ihh, further to any of the above embodiments ofFormula Ihh, L₁₀ is —C(O)—.

In some embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, Y₁₀ is —N═ and R¹⁹⁴ is hydrogen. Insome embodiments of compounds of Formula Ihh, further to any of theabove embodiments of Formula Ihh, Y₁₀ is —C(H)═ and R¹⁹⁴ is fluoro.

In a thirty-fifth aspect, compounds of Formula I having the structureaccording to the following Formula Iii are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₁₁ is —N═ and R²⁰⁰ is hydrogen; or Y₁₁ is —C(H)═ and R²⁰⁰ is        fluoro;    -   L₁₁ is —C(H₂)— or —C(O)—;    -   R¹⁹⁹ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁰³, and —O—R²⁰⁴;    -   R²⁰¹ is hydrogen and R²⁰² is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²⁰² is hydrogen and R²⁰¹ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁰³ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R²⁰⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Iii, R¹⁹⁹ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R¹⁹⁹ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R¹⁹⁹ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰² is hydrogen and R²⁰¹ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰² is hydrogen and R²⁰¹ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iii, further to any of the aboveembodiments of Formula Iii, R²⁰² is hydrogen and R²⁰¹ is lower alkyl. Insome embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰² is hydrogen and R²⁰¹ is C₁₋₃alkyl. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰² is hydrogen and R²⁰¹ ismethyl.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² isfluoro, chloro, bromo. In some embodiments of compounds of Formula Iii,further to any of the above embodiments of Formula Iii, R²⁰¹ is hydrogenand R²⁰² is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² iscycloalkyl. In some embodiments of compounds of Formula Iii, further toany of the above embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰²is cyclopropyl.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iii, further to any of the aboveembodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Iii, further to any of the above embodiments ofFormula Iii, R²⁰¹ is hydrogen and R²⁰² is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² istrifluoromethyl. In some embodiments of compounds of Formula Iii,further to any of the above embodiments of Formula Iii, R²⁰¹ is hydrogenand R²⁰² is methyl. In some embodiments of compounds of Formula Iii,further to any of the above embodiments of Formula Iii, R²⁰¹ is hydrogenand R²⁰² is ethyl.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iii, further to any of the aboveembodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² is lower alkoxy.In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii R²⁰¹ is hydrogen and R²⁰² is C₁₋₃alkoxy. In some embodiments of compounds of Formula Iii, further to anyof the above embodiments of Formula Iii, R²⁰¹ is hydrogen and R²⁰² ismethoxy or ethoxy. In some embodiments of compounds of Formula Iii,further to any of the above embodiments of Formula Iii, R²⁰¹ is hydrogenand R²⁰² is methoxy. In some embodiments of compounds of Formula Iii,further to any of the above embodiments of Formula Iii, R²⁰¹ is hydrogenand R²⁰² is ethoxy.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, L₁₁ is —C(H₂)—. In some embodiments ofcompounds of Formula Iii, further to any of the above embodiments ofFormula Iii, L₁₁ is —C(O)—.

In some embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, Y₁₁ is —N═ and R²⁰⁰ is hydrogen. Insome embodiments of compounds of Formula Iii, further to any of theabove embodiments of Formula Iii, Y₁₁ is —C(H)═ and R²⁰⁰ is fluoro.

In a thirty-sixth aspect, compounds of Formula I having the structureaccording to the following Formula Ijj are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²⁰⁵ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁰⁸, and —O—R²⁰⁹;    -   R²⁰⁶ is hydrogen and R²⁰⁷ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²⁰⁷ is hydrogen and R²⁰⁶ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁰⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R²⁰⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ijj, R²⁰⁵ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁰⁵ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁰⁵ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁷ is hydrogen and R²⁰⁶ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁷ is hydrogen and R²⁰⁶ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ijj, further to any of the aboveembodiments of Formula Ijj, R²⁰⁷ is hydrogen and R²⁰⁶ is lower alkyl. Insome embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁷ is hydrogen and R²⁰⁶ is C₁₋₃alkyl. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁷ is hydrogen and R²⁰⁶ ismethyl.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Ijj,further to any of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogenand R²⁰⁷ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ iscycloalkyl. In some embodiments of compounds of Formula Ijj, further toany of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷is cyclopropyl.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ijj, further to any of the aboveembodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Ijj, further to any of the above embodiments ofFormula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ istrifluoromethyl. In some embodiments of compounds of Formula Ijj,further to any of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogenand R²⁰⁷ is methyl. In some embodiments of compounds of Formula Ijj,further to any of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogenand R²⁰⁷ is ethyl.

In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ijj, further to any of the aboveembodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is lower alkoxy.In some embodiments of compounds of Formula Ijj, further to any of theabove embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Ijj, further to anyof the above embodiments of Formula Ijj, R²⁰⁶ is hydrogen and R²⁰⁷ ismethoxy or ethoxy. In some embodiments of compounds of Formula Ijj,further to any of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogenand R²⁰⁷ is methoxy. In some embodiments of compounds of Formula Ijj,further to any of the above embodiments of Formula Ijj, R²⁰⁶ is hydrogenand R²⁰⁷ is ethoxy.

In a thirty-seventh aspect, compounds of Formula I having the structureaccording to the following Formula Ikk are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²¹⁰ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²¹³, and —O—R²¹⁴;    -   R²¹¹ is hydrogen and R²¹² is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²¹² is hydrogen and R²¹¹ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²¹³ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R²¹⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Ikk, R²¹⁰ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²¹⁰ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²¹⁰ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹² is hydrogen and R²¹¹ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹² is hydrogen and R²¹¹ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ikk, further to any of the aboveembodiments of Formula Ikk, R²¹² is hydrogen and R²¹¹ is lower alkyl. Insome embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹² is hydrogen and R²¹¹ is C₁₋₃alkyl. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹² is hydrogen and R²¹¹ ismethyl.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² isfluoro, chloro, bromo. In some embodiments of compounds of Formula Ikk,further to any of the above embodiments of Formula Ikk, R²¹¹ is hydrogenand R²¹² is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² iscycloalkyl. In some embodiments of compounds of Formula Ikk, further toany of the above embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹²is cyclopropyl.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ikk, further to any of the aboveembodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Ikk, further to any of the above embodiments ofFormula Ikk, R²¹¹ is hydrogen and R²¹² is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² istrifluoromethyl. In some embodiments of compounds of Formula Ikk,further to any of the above embodiments of Formula Ikk, R²¹¹ is hydrogenand R²¹² is methyl. In some embodiments of compounds of Formula Ikk,further to any of the above embodiments of Formula Ikk, R²¹¹ is hydrogenand R²¹² is ethyl.

In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ikk, further to any of the aboveembodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is lower alkoxy.In some embodiments of compounds of Formula Ikk, further to any of theabove embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² is C₁₋₃alkoxy. In some embodiments of compounds of Formula Ikk, further to anyof the above embodiments of Formula Ikk, R²¹¹ is hydrogen and R²¹² ismethoxy or ethoxy. In some embodiments of compounds of Formula Ikk,further to any of the above embodiments of Formula Ikk, R²¹¹ is hydrogenand R²¹² is methoxy. In some embodiments of compounds of Formula Ikk,further to any of the above embodiments of Formula Ikk, R²¹¹ is hydrogenand R²¹² is ethoxy.

In a thirty-eighth aspect, compounds of Formula I having the structureaccording to the following Formula Imm are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²¹⁵ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²¹⁸, and —O—R²¹⁹;    -   R²¹⁶ is hydrogen and R²¹⁷ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²¹⁷ is hydrogen and R²¹⁶ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²¹⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R²¹⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Imm, R²¹⁵ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²¹⁵ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²¹⁵ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁷ is hydrogen and R²¹⁶ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁷ is hydrogen and R²¹⁶ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Imm, further to any of the aboveembodiments of Formula Imm, R²¹⁷ is hydrogen and R²¹⁶ is lower alkyl. Insome embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁷ is hydrogen and R²¹⁶ is C₁₋₃alkyl. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁷ is hydrogen and R²¹⁶ ismethyl.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Imm,further to any of the above embodiments of Formula Imm, R²¹⁶ is hydrogenand R²¹⁷ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ iscycloalkyl. In some embodiments of compounds of Formula Imm, further toany of the above embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷is cyclopropyl.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Imm, further to any of the aboveembodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Imm, further to any of the above embodiments ofFormula Imm, R²¹⁶ is hydrogen and R²¹⁷ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ istrifluoromethyl. In some embodiments of compounds of Formula Imm,further to any of the above embodiments of Formula Imm, R²¹⁶ is hydrogenand R²¹⁷ is methyl. In some embodiments of compounds of Formula Imm,further to any of the above embodiments of Formula Imm, R²¹⁶ is hydrogenand R²¹⁷ is ethyl.

In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Imm, further to any of the aboveembodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is lower alkoxy.In some embodiments of compounds of Formula Imm, further to any of theabove embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Imm, further to anyof the above embodiments of Formula Imm, R²¹⁶ is hydrogen and R²¹⁷ ismethoxy or ethoxy. In some embodiments of compounds of Formula Imm,further to any of the above embodiments of Formula Imm, R²¹⁶ is hydrogenand R²¹⁷ is methoxy. In some embodiments of compounds of Formula Imm,further to any of the above embodiments of Formula Imm, R²¹⁶ is hydrogenand R²¹⁷ is ethoxy.

In a thirty-ninth aspect, compounds of Formula I having the structureaccording to the following Formula Inn are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²²⁰ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²²³, and —O—R²²⁴;    -   R²²¹ is hydrogen and R²²² is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²²² is hydrogen and R²²¹ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²²³ is fluoro or lower alkoxy optionally substituted with one        or more fluoro; and    -   R²²⁴ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy.

In some embodiments of compounds of Formula Inn, R²²⁰ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²²⁰ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²²⁰ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²² is hydrogen and R²²¹ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²² is hydrogen and R²²¹ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Inn, further to any of the aboveembodiments of Formula Inn, R²²² is hydrogen and R²²¹ is lower alkyl. Insome embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²² is hydrogen and R²²¹ is C₁₋₃alkyl. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²² is hydrogen and R²²¹ ismethyl.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²¹ is hydrogen and R²²² isfluoro, chloro, bromo. In some embodiments of compounds of Formula Inn,further to any of the above embodiments of Formula Inn, R²²¹ is hydrogenand R²²² is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²¹ is hydrogen and R²²² iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² iscycloalkyl. In some embodiments of compounds of Formula Inn, further toany of the above embodiments of Formula Inn, R²²¹ is hydrogen and R²²²is cyclopropyl.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Inn, further to any of the aboveembodiments of Formula Inn, R²²¹ is hydrogen and R²²² is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Inn, further to any of the above embodiments ofFormula Inn, R²¹¹ is hydrogen and R²²² is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²¹ is hydrogen and R²²² istrifluoromethyl. In some embodiments of compounds of Formula Inn,further to any of the above embodiments of Formula Inn, R²²¹ is hydrogenand R²²² is methyl. In some embodiments of compounds of Formula Inn,further to any of the above embodiments of Formula Inn, R²²¹ is hydrogenand R²²² is ethyl.

In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Inn, further to any of the aboveembodiments of Formula Inn, R²²¹ is hydrogen and R²²² is lower alkoxy.In some embodiments of compounds of Formula Inn, further to any of theabove embodiments of Formula Inn, R²²¹ is hydrogen and R²²² is C₁₋₃alkoxy. In some embodiments of compounds of Formula Inn, further to anyof the above embodiments of Formula Inn, R²²¹ is hydrogen and R²²² ismethoxy or ethoxy. In some embodiments of compounds of Formula Inn,further to any of the above embodiments of Formula Inn, R²²¹ is hydrogenand R²²² is methoxy. In some embodiments of compounds of Formula Inn,further to any of the above embodiments of Formula Inn, R²²¹ is hydrogenand R²²² is ethoxy.

In a fortieth aspect, compounds of Formula I having the structureaccording to the following Formula Ioo are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₁₂ is —N═ and R²²⁶ is hydrogen; or Y₁₂ is —C(H)═ and R²²⁶ is        fluoro;    -   L₁₂ is —C(H₂)— or —C(O)—;    -   R²²⁵ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R²²⁷ is hydrogen and R²²⁸ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²²⁸ is hydrogen and R²²⁷ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro.

In some embodiments of compounds of Formula Ioo, R²²⁵ is hydrogen,chloro or lower alkyl. In one embodiment, R²²⁵ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R²²⁵ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁸ is hydrogen and R²²⁷ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁸ is hydrogen and R²²⁷ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ioo, further to any of the aboveembodiments of Formula Ioo, R²²⁸ is hydrogen and R²²⁷ is lower alkyl. Insome embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁸ is hydrogen and R²²⁷ is C₁₋₃alkyl. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁸ is hydrogen and R²²⁷ ismethyl.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Ioo,further to any of the above embodiments of Formula Ioo, R²²⁷ is hydrogenand R²²⁸ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ iscycloalkyl. In some embodiments of compounds of Formula Ioo, further toany of the above embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸is cyclopropyl.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ioo, further to any of the aboveembodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Ioo, further to any of the above embodiments ofFormula Ioo, R²²⁷ is hydrogen and R²²⁸ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ istrifluoromethyl. In some embodiments of compounds of Formula Ioo,further to any of the above embodiments of Formula Ioo, R²²⁷ is hydrogenand R²²⁸ is methyl. In some embodiments of compounds of Formula Ioo,further to any of the above embodiments of Formula Ioo, R²²⁷ is hydrogenand R²²⁸ is ethyl.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ioo, further to any of the aboveembodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is lower alkoxy.In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Ioo, further to anyof the above embodiments of Formula Ioo, R²²⁷ is hydrogen and R²²⁸ ismethoxy or ethoxy. In some embodiments of compounds of Formula Ioo,further to any of the above embodiments of Formula Ioo, R²²⁷ is hydrogenand R²²⁸ is methoxy. In some embodiments of compounds of Formula Ioo,further to any of the above embodiments of Formula Ioo, R²²⁷ is hydrogenand R²²⁸ is ethoxy.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, L₁₂ is —C(H₂)—. In some embodiments ofcompounds of Formula Ioo, further to any of the above embodiments ofFormula Ioo, L₁₂ is —C(O)—.

In some embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, Y₁₂ is —N═ and R²²⁶ is hydrogen. Insome embodiments of compounds of Formula Ioo, further to any of theabove embodiments of Formula Ioo, Y₁₂ is —C(H)═ and R²²⁶ is fluoro.

In a forty-first aspect, compounds of Formula I having the structureaccording to the following Formula Ipp are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²²⁹ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R²³⁰ is hydrogen and R²³¹ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²³¹ is hydrogen and R²³⁰ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro.

In some embodiments of compounds of Formula Ipp, R²²⁹ is hydrogen,chloro or lower alkyl. In one embodiment, R²²⁹ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R²²⁹ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³¹ is hydrogen and R²³⁰ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³¹ is hydrogen and R²³⁰ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ipp, further to any of the aboveembodiments of Formula Ipp, R²³¹ is hydrogen and R²³⁰ is lower alkyl. Insome embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³¹ is hydrogen and R²³⁰ is C₁₋₃alkyl. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³¹ is hydrogen and R²³⁰ ismethyl.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Ipp,further to any of the above embodiments of Formula Ipp, R²³⁰ is hydrogenand R²³¹ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ iscycloalkyl. In some embodiments of compounds of Formula Ipp, further toany of the above embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹is cyclopropyl.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ipp, further to any of the aboveembodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Ipp, further to any of the above embodiments ofFormula Ipp, R²³⁰ is hydrogen and R²³¹ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ istrifluoromethyl. In some embodiments of compounds of Formula Ipp,further to any of the above embodiments of Formula Ipp, R²³⁰ is hydrogenand R²³¹ is methyl. In some embodiments of compounds of Formula Ipp,further to any of the above embodiments of Formula Ipp, R²³⁰ is hydrogenand R²³¹ is ethyl.

In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Ipp, further to any of the aboveembodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is lower alkoxy.In some embodiments of compounds of Formula Ipp, further to any of theabove embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Ipp, further to anyof the above embodiments of Formula Ipp, R²³⁰ is hydrogen and R²³¹ ismethoxy or ethoxy. In some embodiments of compounds of Formula Ipp,further to any of the above embodiments of Formula Ipp, R²³⁰ is hydrogenand R²³¹ is methoxy. In some embodiments of compounds of Formula Ipp,further to any of the above embodiments of Formula Ipp, R²³⁰ is hydrogenand R²³¹ is ethoxy.

In a forty-second aspect, compounds of Formula I having the structureaccording to the following Formula Iqq are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²³² is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R²³³ is hydrogen and R²³⁴ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²³⁴ is hydrogen and R²³³ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro.

In some embodiments of compounds of Formula Iqq, R²³² is hydrogen,chloro or lower alkyl. In one embodiment, R²³² is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R²³² is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³⁴ is hydrogen and R²³³ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³⁴ is hydrogen and R²³³ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iqq, further to any of the aboveembodiments of Formula Iqq, R²³⁴ is hydrogen and R²³³ is lower alkyl. Insome embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³⁴ is hydrogen and R²³³ is C₁₋₃alkyl. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³⁴ is hydrogen and R²³³ ismethyl.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Iqq,further to any of the above embodiments of Formula Iqq, R²³³ is hydrogenand R²³⁴ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ iscycloalkyl. In some embodiments of compounds of Formula Iqq, further toany of the above embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴is cyclopropyl.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iqq, further to any of the aboveembodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Iqq, further to any of the above embodiments ofFormula Iqq, R²³³ is hydrogen and R²³⁴ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ istrifluoromethyl. In some embodiments of compounds of Formula Iqq,further to any of the above embodiments of Formula Iqq, R²³³ is hydrogenand R²³⁴ is methyl. In some embodiments of compounds of Formula Iqq,further to any of the above embodiments of Formula Iqq, R²³³ is hydrogenand R²³⁴ is ethyl.

In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iqq, further to any of the aboveembodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is lower alkoxy.In some embodiments of compounds of Formula Iqq, further to any of theabove embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Iqq, further to anyof the above embodiments of Formula Iqq, R²³³ is hydrogen and R²³⁴ ismethoxy or ethoxy. In some embodiments of compounds of Formula Iqq,further to any of the above embodiments of Formula Iqq, R²³³ is hydrogenand R²³⁴ is methoxy. In some embodiments of compounds of Formula Iqq,further to any of the above embodiments of Formula Iqq, R²³³ is hydrogenand R²³⁴ is ethoxy.

In a forty-third aspect, compounds of Formula I having the structureaccording to the following Formula Irr are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²³⁵ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R²³⁶ is hydrogen and R²³⁷ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²³⁷ is hydrogen and R²³⁶ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro.

In some embodiments of compounds of Formula Irr, R²³⁵ is hydrogen,chloro or lower alkyl. In one embodiment, R²³⁵ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R²³⁵ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁷ is hydrogen and R²³⁶ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Irr, further to anyof the above embodiments of Formula Irr, R²³⁷ is hydrogen and R²³⁶ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Irr, further to any of the aboveembodiments of Formula Irr, R²³⁷ is hydrogen and R²³⁶ is lower alkyl. Insome embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁷ is hydrogen and R²³⁶ is C₁₋₃alkyl. In some embodiments of compounds of Formula Irr, further to anyof the above embodiments of Formula Irr, R²³⁷ is hydrogen and R²³⁶ ismethyl.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Irr, further to anyof the above embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Irr,further to any of the above embodiments of Formula Irr, R²³⁶ is hydrogenand R²³⁷ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Irr, further to anyof the above embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ iscycloalkyl. In some embodiments of compounds of Formula Irr, further toany of the above embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷is cyclopropyl.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Irr, further to any of the aboveembodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Irr, further to any of the above embodiments ofFormula Irr, R²³⁶ is hydrogen and R²³⁷ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Irr, further to anyof the above embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ istrifluoromethyl. In some embodiments of compounds of Formula Irr,further to any of the above embodiments of Formula Irr, R²³⁶ is hydrogenand R²³⁷ is methyl. In some embodiments of compounds of Formula Irr,further to any of the above embodiments of Formula Irr, R²³⁶ is hydrogenand R²³⁷ is ethyl.

In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Irr, further to any of the aboveembodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ is lower alkoxy.In some embodiments of compounds of Formula Irr, further to any of theabove embodiments of Formula Irr R²³⁶ is hydrogen and R²³⁷ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Irr further to anyof the above embodiments of Formula Irr, R²³⁶ is hydrogen and R²³⁷ ismethoxy or ethoxy. In some embodiments of compounds of Formula Irr,further to any of the above embodiments of Formula Irr, R²³⁶ is hydrogenand R²³⁷ is methoxy. In some embodiments of compounds of Formula Irr,further to any of the above embodiments of Formula Irr, R²³⁶ is hydrogenand R²³⁷ is ethoxy.

In a forty-fourth aspect, compounds of Formula I having the structureaccording to the following Formula Iss are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²³⁸ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R²³⁹ is hydrogen and R²⁴⁰ is hydrogen, fluoro, chloro, bromo,        cycloalkyl, lower alkyl optionally substituted with one or more        fluoro, or lower alkoxy optionally substituted with one or more        fluoro; or    -   R²⁴⁰ is hydrogen and R²³⁹ is fluoro, chloro, bromo, cycloalkyl,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro.

In some embodiments of compounds of Formula Iss, R²³⁸ is hydrogen,chloro or lower alkyl. In one embodiment, R²³⁸ is hydrogen, chloro orC₁₋₃ alkyl. In one embodiment, R²³⁸ is hydrogen, chloro or methyl.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²⁴⁰ is hydrogen and R²³⁹ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²⁴⁰ is hydrogen and R²³⁹ islower alkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iss, further to any of the aboveembodiments of Formula Iss, R²⁴⁰ is hydrogen and R²³⁹ is lower alkyl. Insome embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²⁴⁰ is hydrogen and R²³⁹ is C₁₋₃alkyl. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²⁴⁰ is hydrogen and R²³⁹ ismethyl.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is fluoro,chloro, bromo, cycloalkyl, lower alkyl optionally substituted with oneor more fluoro, or lower alkoxy optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ isfluoro, chloro, bromo. In some embodiments of compounds of Formula Iss,further to any of the above embodiments of Formula Iss, R²³⁹ is hydrogenand R²⁴⁰ is cycloalkyl, lower alkyl optionally substituted with one ormore fluoro, or lower alkoxy optionally substituted with one or morefluoro.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ iscycloalkyl or lower alkyl optionally substituted with one or morefluoro. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ iscycloalkyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ iscyclopropyl or C₁₋₃ alkyl optionally substituted with 1, 2, or 3 fluoro.In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ iscyclopropyl, trifluoromethyl, methyl or ethyl.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ iscycloalkyl. In some embodiments of compounds of Formula Iss, further toany of the above embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰is cyclopropyl.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is loweralkyl optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iss, further to any of the aboveembodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 fluoro. In some embodiments ofcompounds of Formula Iss, further to any of the above embodiments ofFormula Iss, R²³⁹ is hydrogen and R²⁴⁰ is trifluoromethyl, methyl orethyl. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ istrifluoromethyl. In some embodiments of compounds of Formula Iss,further to any of the above embodiments of Formula Iss, R²³⁹ is hydrogenand R²⁴⁰ is methyl. In some embodiments of compounds of Formula Iss,further to any of the above embodiments of Formula Iss, R²³⁹ is hydrogenand R²⁴⁰ is ethyl.

In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is loweralkoxy optionally substituted with one or more fluoro. In someembodiments of compounds of Formula Iss, further to any of the aboveembodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is lower alkoxy.In some embodiments of compounds of Formula Iss, further to any of theabove embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ is C₁₋₃alkoxy. In some embodiments of compounds of Formula Iss, further to anyof the above embodiments of Formula Iss, R²³⁹ is hydrogen and R²⁴⁰ ismethoxy or ethoxy. In some embodiments of compounds of Formula Iss,further to any of the above embodiments of Formula Iss, R²³⁹ is hydrogenand R²⁴⁰ is methoxy. In some embodiments of compounds of Formula Iss,further to any of the above embodiments of Formula Iss, R²³⁹ is hydrogenand R²⁴⁰ is ethoxy.

In a forty-fifth aspect, compounds of Formula I having the structureaccording to the following Formula Itt are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   X₅ is —N═, —C(H)═, or —C(R²⁴¹)═;    -   Y₁₃ is —N═ and R²⁴³ is hydrogen; or Y₁₃ is —C(H)═ and R²⁴³ is        fluoro;    -   L₁₃ is —C(H₂)— or —C(O)—;    -   when X₅ is —C(R²⁴¹)═, R²⁴² is hydrogen;    -   when X₅ is —N═ or —C(H)═, R²⁴² is selected from the group        consisting of hydrogen, cycloalkyl, lower alkyl optionally        substituted with one or more R²⁴⁷, and —O—R²⁴⁸;    -   R²⁴¹ is fluoro, chloro, or lower alkyl optionally substituted        with one or more fluoro;    -   R²⁴⁴ and R²⁴⁵ are hydrogen and R²⁴⁶ is selected from the group        consisting of fluoro, chloro, —O—R²⁴⁹, —S—R²⁵⁰, —S(O₂)—R²⁵¹, and        lower alkyl optionally substituted with one or more R²⁵²; or    -   R²⁴⁴ and R²⁴⁶ are hydrogen and R²⁴⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁴⁵ and R²⁴⁶ are hydrogen and R²⁴⁴ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁴⁴ is hydrogen, R²⁴⁵ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁴⁶ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁴⁷ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁴⁸ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R²⁴⁹, R²⁵⁰ and R²⁵¹ are lower alkyl optionally substituted with        one or more fluoro; and    -   R²⁵² is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Itt, X₅ is —N═ and R²⁴² isselected from the group consisting of hydrogen, cycloalkyl, lower alkyloptionally substituted with one or more R²⁴⁷, and —O—R²⁴⁸. In oneembodiment, X₅ is —N═ and R²⁴² is selected from the group consisting ofcycloalkyl, lower alkyl, lower alkoxy, and lower alkoxy substituted withlower alkoxy. In one embodiment, X₅ is —N═ and R²⁴² is selected from thegroup consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃ alkoxy, and C₁₋₃alkoxy substituted with C₁₋₃ alkoxy. In one embodiment, X₅ is —N═ andR²⁴² is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Itt, X₅ is —C(H)═ or—C(R²⁴¹)═ and R²⁴¹ is fluoro, chloro, or lower alkyl optionallysubstituted with one or more fluoro. In one embodiment, X₅ is —C(H)═ or—C(R²⁴¹)═ and R²⁴¹ is chloro or lower alkyl. In one embodiment, X₅ is—C(H)═ or —C(R²⁴¹)═ and R²⁴¹ is chloro or C₁₋₃ alkyl. In one embodiment,X₅ is —C(H)═ or —C(R²⁴¹)═ and R²⁴¹ is chloro or methyl.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁴ and R²⁴⁵ are hydrogen and R²⁴⁶ isselected from the group consisting of fluoro, chloro, —O—R²⁴⁹, —S—R²⁵⁰,—S(O₂)—R²⁵¹, and lower alkyl optionally substituted with one or moreR²⁵². In some embodiments of compounds of Formula Itt, further to any ofthe above embodiments of Formula Itt, R²⁴⁴ and R²⁴⁵ are hydrogen andR²⁴⁶ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Itt, further to any of the above embodiments ofFormula Itt, R²⁴⁴ and R²⁴⁵ are hydrogen and R²⁴⁶ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁴ and R²⁴⁶ are hydrogen and R²⁴⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁴ and R²⁴⁶ are hydrogen and R²⁴⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁵ and R²⁴⁶ are hydrogen and R²⁴⁴ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁵ and R²⁴⁶ are hydrogen and R²⁴⁴ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁴ is hydrogen, R²⁴⁵ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁴⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, R²⁴⁴ is hydrogen, R²⁴⁵ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁴⁶ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Itt,further to any of the above embodiments of Formula Itt, R²⁴⁴ ishydrogen, R²⁴⁵ is fluoro, chloro, or lower alkoxy and R²⁴⁶ is fluoro,chloro, or lower alkoxy.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, L₁₃ is —C(H₂)—. In some embodiments ofcompounds of Formula Itt, further to any of the above embodiments ofFormula Itt, L₁₃ is —C(O)—.

In some embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, Y₁₃ is —N═ and R²⁴³ is hydrogen. Insome embodiments of compounds of Formula Itt, further to any of theabove embodiments of Formula Itt, Y₁₃ is —C(H)═ and R²⁴³ is fluoro.

In a forty-sixth aspect, compounds of Formula I having the structureaccording to the following Formula Iuu are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₁₄ is —N═ and R²⁵⁴ is hydrogen; or Y₁₄ is —C(H)═ and R²⁵⁴ is        fluoro;    -   L₁₄ is —C(H₂)— or —C(O)—;    -   R²⁵³ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁵⁸, and —O—R²⁵⁹;    -   R²⁵⁵ and R²⁵⁶ are hydrogen and R²⁵⁷ is selected from the group        consisting of fluoro, chloro, —O—R²⁶⁰, —S—R²⁶¹, —S(O₂)—R²⁶², and        lower alkyl optionally substituted with one or more R²⁶³; or    -   R²⁵⁵ and R²⁵⁷ are hydrogen and R²⁵⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁵⁶ and R²⁵⁷ are hydrogen and R²⁵⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁵⁵ is hydrogen, R²⁵⁶ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁵⁷ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁵⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁵⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R²⁶⁰, R²⁶¹ and R²⁶² are lower alkyl optionally substituted with        one or more fluoro; and    -   R²⁶³ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iuu, R²⁵³ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁵³ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁵³ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁵ and R²⁵⁶ are hydrogen and R²⁵⁷ isselected from the group consisting of fluoro, chloro, —O—R²⁶⁰, —S—R²⁶¹,—S(O₂)—R²⁶², and lower alkyl optionally substituted with one or moreR²⁶³. In some embodiments of compounds of Formula Iuu, further to any ofthe above embodiments of Formula Iuu, R²⁵⁵ and R²⁵⁶ are hydrogen andR²⁵⁷ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iuu, further to any of the above embodiments ofFormula Iuu, R²⁵⁵ and R²⁵⁶ are hydrogen and R²⁵⁷ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁵ and R²⁵⁷ are hydrogen and R²⁵⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁵ and R²⁵⁷ are hydrogen and R²⁵⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁶ and R²⁵⁷ are hydrogen and R²⁵⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁶ and R²⁵⁷ are hydrogen and R²⁵⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁵ is hydrogen, R²⁵⁶ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁵⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, R²⁵⁵ is hydrogen, R²⁵⁶ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁵⁷ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iuu,further to any of the above embodiments of Formula Iuu, R²⁵⁵ ishydrogen, R²⁵⁶ is fluoro, chloro, or lower alkoxy and R²⁵⁷ is fluoro,chloro, or lower alkoxy.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, L₁₄ is —C(H₂)—. In some embodiments ofcompounds of Formula Iuu, further to any of the above embodiments ofFormula Iuu, L₁₄ is —C(O)—.

In some embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, Y₁₄ is —N═ and R²⁵⁴ is hydrogen. Insome embodiments of compounds of Formula Iuu, further to any of theabove embodiments of Formula Iuu, Y₁₄ is —C(H)═ and R²⁵⁴ is fluoro.

In a forty-seventh aspect, compounds of Formula I having the structureaccording to the following Formula Ivv are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²⁶⁴ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁶⁸, and —O—R²⁶⁹;    -   R²⁶⁵ and R²⁶⁶ are hydrogen and R²⁶⁷ is selected from the group        consisting of fluoro, chloro, —O—R²⁷⁰, —S—R²⁷¹, —S(O₂)—R²⁷², and        lower alkyl optionally substituted with one or more    -   R²⁷³; or    -   R²⁶⁵ and R²⁶⁷ are hydrogen and R²⁶⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁶⁶ and R²⁶⁷ are hydrogen and R²⁶⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁶⁵ is hydrogen, R²⁶⁶ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁶⁷ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁶⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁶⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R²⁷⁰, R²⁷¹ and R²⁷² are lower alkyl optionally substituted with        one or more fluoro; and    -   R²⁷³ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Ivv, R²⁶⁴ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁶⁴ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁶⁴ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁵ and R²⁶⁶ are hydrogen and R²⁶⁷ isselected from the group consisting of fluoro, chloro, —O—R²⁷⁰, —S—R²⁷¹,—S(O₂)—R²⁷², and lower alkyl optionally substituted with one or moreR²⁷³. In some embodiments of compounds of Formula Ivv, further to any ofthe above embodiments of Formula Ivv, R²⁶⁵ and R²⁶⁶ are hydrogen andR²⁶⁷ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Ivv, further to any of the above embodiments ofFormula Ivv, R²⁶⁵ and R²⁶⁶ are hydrogen and R²⁶⁷ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁵ and R²⁶⁷ are hydrogen and R²⁶⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁵ and R²⁶⁷ are hydrogen and R²⁶⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁶ and R²⁶⁷ are hydrogen and R²⁶⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁶ and R²⁶⁷ are hydrogen and R²⁶⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁵ is hydrogen, R²⁶⁶ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁶⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ivv, further to any of theabove embodiments of Formula Ivv, R²⁶⁵ is hydrogen, R²⁶⁶ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁶⁷ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Ivv,further to any of the above embodiments of Formula Ivv, R²⁶⁵ ishydrogen, R²⁶⁶ is fluoro, chloro, or lower alkoxy and R²⁶⁷ is fluoro,chloro, or lower alkoxy.

In a forty-eighth aspect, compounds of Formula I having the structureaccording to the following Formula Iww are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²⁷⁴ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁷⁸, and —O—R²⁷⁹;    -   R²⁷⁵ and R²⁷⁶ are hydrogen and R²⁷⁷ is selected from the group        consisting of fluoro, chloro, —O—R²⁸⁰, —S—R²⁸¹, —S(O₂)—R²⁸², and        lower alkyl optionally substituted with one or more R²⁸³; or    -   R²⁷⁵ and R²⁷⁷ are hydrogen and R²⁷⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁷⁶ and R²⁷⁷ are hydrogen and R²⁷⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁷⁵ is hydrogen, R²⁷⁶ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁷⁷ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁷⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁷⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R²⁸⁰, R²⁸¹ and R²⁸² are lower alkyl optionally substituted with        one or more fluoro; and    -   R²⁸³ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iww, R²⁷⁴ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁷⁴ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁷⁴ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁵ and R²⁷⁶ are hydrogen and R²⁷⁷ isselected from the group consisting of fluoro, chloro, —O—R²⁸⁰, —S—R²⁸¹,—S(O₂)—R²⁸², and lower alkyl optionally substituted with one or moreR²⁸³. In some embodiments of compounds of Formula Iww, further to any ofthe above embodiments of Formula Iww, R²⁷⁵ and R²⁷⁶ are hydrogen andR²⁷⁷ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iww, further to any of the above embodiments ofFormula Iww, R²⁷⁵ and R²⁷⁶ are hydrogen and R²⁷⁷ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁵ and R²⁷⁷ are hydrogen and R²⁷⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁵ and R²⁷⁷ are hydrogen and R²⁷⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁶ and R²⁷⁷ are hydrogen and R²⁷⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁶ and R²⁷⁷ are hydrogen and R²⁷⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁵ is hydrogen, R²⁷⁶ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁷⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iww, further to any of theabove embodiments of Formula Iww, R²⁷⁵ is hydrogen, R²⁷⁶ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁷⁷ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iww,further to any of the above embodiments of Formula Iww, R²⁷⁵ ishydrogen, R²⁷⁶ is fluoro, chloro, or lower alkoxy and R²⁷⁷ is fluoro,chloro, or lower alkoxy.

In a forty-ninth aspect, compounds of Formula I having the structureaccording to the following Formula Ixx are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²⁸⁴ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁸⁸, and —O—R²⁸⁹;    -   R²⁸⁵ and R²⁸⁶ are hydrogen and R²⁸⁷ is selected from the group        consisting of fluoro, chloro, —O—R²⁹⁰, —S—R²⁹¹, —S(O₂)—R²⁹², and        lower alkyl optionally substituted with one or more R²⁹³; or    -   R²⁸⁵ and R²⁸⁷ are hydrogen and R²⁸⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁸⁶ and R²⁸⁷ are hydrogen and R²⁸⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁸⁵ is hydrogen, R²⁸⁶ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁸⁷ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁸⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁸⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R²⁹⁰, R²⁹¹ and R²⁹² are lower alkyl optionally substituted with        one or more fluoro; and    -   R²⁹³ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Ixx, R²⁸⁴ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁸⁴ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁸⁴ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁵ and R²⁸⁶ are hydrogen and R²⁸⁷ isselected from the group consisting of fluoro, chloro, —O—R²⁹⁰, —S—R²⁹¹,—S(O₂)—R²⁹², and lower alkyl optionally substituted with one or moreR²⁹³. In some embodiments of compounds of Formula Ixx, further to any ofthe above embodiments of Formula Ixx, R²⁸⁵ and R²⁸⁶ are hydrogen andR²⁸⁷ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Ixx, further to any of the above embodiments ofFormula Ixx, R²⁸⁵ and R²⁸⁶ are hydrogen and R²⁸⁷ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁵ and R²⁸⁷ are hydrogen and R²⁸⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁵ and R²⁸⁷ are hydrogen and R²⁸⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁶ and R²⁸⁷ are hydrogen and R²⁸⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁶ and R²⁸⁷ are hydrogen and R²⁸⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁵ is hydrogen, R²⁸⁶ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁸⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Ixx, further to any of theabove embodiments of Formula Ixx, R²⁸⁵ is hydrogen, R²⁸⁶ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁸⁷ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Ixx,further to any of the above embodiments of Formula Ixx, R²⁸⁵ ishydrogen, R²⁸⁶ is fluoro, chloro, or lower alkoxy and R²⁸⁷ is fluoro,chloro, or lower alkoxy.

In a fiftieth aspect, compounds of Formula I having the structureaccording to the following Formula Iyy are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R²⁹⁴ is selected from the group consisting of hydrogen,        cycloalkyl, lower alkyl optionally substituted with one or more        R²⁹⁸, and —O—R²⁹⁹;    -   R²⁹⁵ and R²⁹⁶ are hydrogen and R²⁹⁷ is selected from the group        consisting of fluoro, chloro, —O—R³⁰⁰, —S—R³⁰¹, —S(O₂)—R³⁰², and        lower alkyl optionally substituted with one or more R³⁰³; or    -   R²⁹⁵ and R²⁹⁷ are hydrogen and R²⁹⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁹⁶ and R²⁹⁷ are hydrogen and R²⁹⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R²⁹⁵ is hydrogen, R²⁹⁶ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R²⁹⁷ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R²⁹⁸ is fluoro or lower alkoxy optionally substituted with one        or more fluoro;    -   R²⁹⁹ is lower alkyl, lower alkyl substituted with one or more        fluoro, or lower alkyl substituted with lower alkoxy;    -   R³⁰⁰, R³⁰¹ and R³⁰² are lower alkyl optionally substituted with        one or more fluoro; and    -   R³⁰³ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iyy, R²⁹⁴ is selected fromthe group consisting of cycloalkyl, lower alkyl, lower alkoxy, and loweralkoxy substituted with lower alkoxy. In one embodiment, R²⁹⁴ isselected from the group consisting of C₃₋₆ cycloalkyl, C₁₋₃ alkyl, C₁₋₃alkoxy, and C₁₋₃ alkoxy substituted with C₁₋₃ alkoxy. In one embodiment,R²⁹⁴ is selected from the group consisting of methyl, cyclopropyl,methoxy, ethoxy, and 2-methoxy-ethoxy.

In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁵ and R²⁹⁶ are hydrogen and R²⁹⁷ isselected from the group consisting of fluoro, chloro, —O—R³⁰⁰, —S—R³⁰¹,—S(O₂)—R³⁰², and lower alkyl optionally substituted with one or moreR³⁰³. In some embodiments of compounds of Formula Iyy, further to any ofthe above embodiments of Formula Iyy, R²⁹⁵ and R²⁹⁶ are hydrogen andR²⁹⁷ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iyy, further to any of the above embodiments ofFormula Iyy, R²⁹⁵ and R²⁹⁶ are hydrogen and R²⁹⁷ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁵ and R²⁹⁷ are hydrogen and R²⁹⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁵ and R²⁹⁷ are hydrogen and R²⁹⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁶ and R²⁹⁷ are hydrogen and R²⁹⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁶ and R²⁹⁷ are hydrogen and R²⁹⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁵ is hydrogen, R²⁹⁶ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R²⁹⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iyy, further to any of theabove embodiments of Formula Iyy, R²⁹⁵ is hydrogen, R²⁹⁶ is fluoro,chloro, lower alkyl or lower alkoxy and R²⁹⁷ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iyy,further to any of the above embodiments of Formula Iyy, R²⁹⁵ ishydrogen, R²⁹⁶ is fluoro, chloro, or lower alkoxy and R²⁹⁷ is fluoro,chloro, or lower alkoxy.

In a fifty-first aspect, compounds of Formula I having the structureaccording to the following Formula Izz are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   Y₁₅ is —N═ and R³⁰⁵ is hydrogen; or Y₁₅ is —C(H)═ and R³⁰⁵ is        fluoro;    -   L₁₅ is —C(H₂)— or —C(O)—;    -   R³⁰⁴ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R³⁰⁶ and R³⁰⁷ are hydrogen and R³⁰⁸ is selected from the group        consisting of fluoro, chloro, —O—R³⁰⁹, —S—R³¹⁰, —S(O₂)—R³¹¹ and        lower alkyl optionally substituted with one or more R³¹²; or    -   R³⁰⁶ and R³⁰⁸ are hydrogen and R³⁰⁷ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³⁰⁷ and R³⁰⁸ are hydrogen and R³⁰⁶ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³⁰⁶ is hydrogen, R³⁰⁷ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R³⁰⁸ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R³⁰⁹, R³¹⁰ and R³¹¹ are lower alkyl optionally substituted with        one or more fluoro; and    -   R³¹² is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Izz, R³⁰⁴ is hydrogen,chloro or lower alkyl. In one embodiment, R³⁰⁴ is chloro or C₁₋₃ alkyl.In one embodiment, R³⁰⁴ is chloro or methyl.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁶ and R³⁰⁷ are hydrogen and R³⁰⁸ isselected from the group consisting of fluoro, chloro, —O—R³⁰⁹, —S—R³¹⁰,—S(O₂)—R³¹¹, and lower alkyl optionally substituted with one or moreR³¹². In some embodiments of compounds of Formula Izz, further to any ofthe above embodiments of Formula Izz, R³⁰⁶ and R³⁰⁷ are hydrogen andR³⁰⁸ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Izz, further to any of the above embodiments ofFormula Izz, R³⁰⁶ and R³⁰⁷ are hydrogen and R³⁰⁸ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁶ and R³⁰⁸ are hydrogen and R³⁰⁷ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁶ and R³⁰⁸ are hydrogen and R³⁰⁷ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁷ and R³⁰⁸ are hydrogen and R³⁰⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁷ and R³⁰⁸ are hydrogen and R³⁰⁶ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁶ is hydrogen, R³⁰⁷ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R³⁰⁸ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, R³⁰⁶ is hydrogen, R³⁰⁷ is fluoro,chloro, lower alkyl or lower alkoxy and R³⁰⁸ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Izz,further to any of the above embodiments of Formula Izz, R³⁰⁶ ishydrogen, R³⁰⁷ is fluoro, chloro, or lower alkoxy and R³⁰⁸ is fluoro,chloro, or lower alkoxy.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, L₁₅ is —C(H₂)—. In some embodiments ofcompounds of Formula Izz, further to any of the above embodiments ofFormula Izz, L₁₅ is —C(O)—.

In some embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, Y₁₅ is —N═ and R³⁰⁵ is hydrogen. Insome embodiments of compounds of Formula Izz, further to any of theabove embodiments of Formula Izz, Y₁₅ is —C(H)═ and R³⁰⁵ is fluoro.

In a fifty-second aspect, compounds of Formula I having the structureaccording to the following Formula Iab are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R³¹³ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R³¹⁴ and R³¹⁵ are hydrogen and R³¹⁶ is selected from the group        consisting of fluoro, chloro, —O—R³¹⁷, —S—R³¹⁸, —S(O₂)—R³¹⁹, and        lower alkyl optionally substituted with one or more R³²⁰; or    -   R³¹⁴ and R³¹⁶ are hydrogen and R³¹⁵ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³¹⁵ and R³¹⁶ are hydrogen and R³¹⁴ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³¹⁴ is hydrogen, R³¹⁵ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R³¹⁶ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R³¹⁷, R³¹⁸ and R³¹⁹ are lower alkyl optionally substituted with        one or more fluoro; and    -   R³²⁰ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iab, R³¹³ is hydrogen,chloro or lower alkyl. In one embodiment, R³¹³ is chloro or C₁₋₃ alkyl.In one embodiment, R³¹³ is chloro or methyl.

In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁴ and R³¹⁵ are hydrogen and R³¹⁶ isselected from the group consisting of fluoro, chloro, —O—R³¹⁷, —S—R³¹⁸,—S(O₂)—R³¹⁹, and lower alkyl optionally substituted with one or moreR³²⁰. In some embodiments of compounds of Formula Iab, further to any ofthe above embodiments of Formula Iab, R³¹⁴ and R³¹⁵ are hydrogen andR³¹⁶ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iab, further to any of the above embodiments ofFormula Iab, R³¹⁴ and R³¹⁵ are hydrogen and R³¹⁶ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁴ and R³¹⁶ are hydrogen and R³¹⁵ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁴ and R³¹⁶ are hydrogen and R³¹⁵ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁵ and R³¹⁶ are hydrogen and R³¹⁴ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁵ and R³¹⁶ are hydrogen and R³¹⁴ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁴ is hydrogen, R³¹⁵ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R³¹⁶ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iab, further to any of theabove embodiments of Formula Iab, R³¹⁴ is hydrogen, R³¹⁵ is fluoro,chloro, lower alkyl or lower alkoxy and R³¹⁶ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iab,further to any of the above embodiments of Formula Iab, R³¹⁴ ishydrogen, R³¹⁵ is fluoro, chloro, or lower alkoxy and R³¹⁶ is fluoro,chloro, or lower alkoxy.

In a fifty-third aspect, compounds of Formula I having the structureaccording to the following Formula Iac are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R³²¹ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R³²² and R³²³ are hydrogen and R³²⁴ is selected from the group        consisting of fluoro, chloro, —O—R³²⁵, —S—R³²⁶, —S(O₂)—R³²⁷, and        lower alkyl optionally substituted with one or more R³²⁸; or    -   R³²² and R³²⁴ are hydrogen and R³²³ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³²³ and R³²⁴ are hydrogen and R³²² is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³²² is hydrogen, R³²³ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R³²⁴ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R³²⁵, R³²⁶ and R³²⁷ are lower alkyl optionally substituted with        one or more fluoro; and    -   R³²⁸ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iac, R³²¹ is hydrogen,chloro or lower alkyl. In one embodiment, R³²¹ is chloro or C₁₋₃ alkyl.In one embodiment, R³²¹ is chloro or methyl.

In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²² and R³²³ are hydrogen and R³²⁴ isselected from the group consisting of fluoro, chloro, —O—R³²⁵, —S—R³²⁶,—S(O₂)—R³²⁷, and lower alkyl optionally substituted with one or moreR³²⁸. In some embodiments of compounds of Formula Iac, further to any ofthe above embodiments of Formula Iac, R³²² and R³²³ are hydrogen andR³²⁴ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iac, further to any of the above embodiments ofFormula Iac, R³²² and R³²³ are hydrogen and R³²⁴ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²² and R³²⁴ are hydrogen and R³²³ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²² and R³²⁴ are hydrogen and R³²³ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²³ and R³²⁴ are hydrogen and R³²² isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²³ and R³²⁴ are hydrogen and R³²² isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²² is hydrogen, R³²³ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R³²⁴ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iac, further to any of theabove embodiments of Formula Iac, R³²² is hydrogen, R³²³ is fluoro,chloro, lower alkyl or lower alkoxy and R³²⁴ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iac,further to any of the above embodiments of Formula Iac, R³²² ishydrogen, R³²³ is fluoro, chloro, or lower alkoxy and R³²⁴ is fluoro,chloro, or lower alkoxy.

In a fifty-fourth aspect, compounds of Formula I having the structureaccording to the following Formula Iad are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R³²⁹ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R³³⁰ and R³³¹ are hydrogen and R³³² is selected from the group        consisting of fluoro, chloro, —O—R³³³, —S—R³³⁴, —S(O₂)—R³³⁵, and        lower alkyl optionally substituted with one or more R³³⁶; or    -   R³³⁰ and R³³² are hydrogen and R³³¹ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³³¹ and R³³² are hydrogen and R³³⁰ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³³⁰ is hydrogen, R³³¹ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R³³² is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R³³³, R³³⁴ and R³³⁵ are lower alkyl optionally substituted with        one or more fluoro; and    -   R³³⁶ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iad, R³²⁹ is hydrogen,chloro or lower alkyl. In one embodiment, R³²⁹ is chloro or C₁₋₃ alkyl.In one embodiment, R³²⁹ is chloro or methyl.

In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³⁰ and R³³¹ are hydrogen and R³³² isselected from the group consisting of fluoro, chloro, —O—R³³³, —S—R³³⁴,—S(O₂)—R³³⁵, and lower alkyl optionally substituted with one or moreR³³⁶. In some embodiments of compounds of Formula Iad, further to any ofthe above embodiments of Formula Iad, R³³⁰ and R³³¹ are hydrogen andR³³² is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iad, further to any of the above embodiments ofFormula Iad, R³³⁰ and R³³¹ are hydrogen and R³³² is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³⁰ and R³³² are hydrogen and R³³¹ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³⁰ and R³³² are hydrogen and R³³¹ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³¹ and R³³² are hydrogen and R³³⁰ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³¹ and R³³² are hydrogen and R³³⁰ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³⁰ is hydrogen, R³³¹ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R³³² isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iad, further to any of theabove embodiments of Formula Iad, R³³⁰ is hydrogen, R³³¹ is fluoro,chloro, lower alkyl or lower alkoxy and R³³² is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iad,further to any of the above embodiments of Formula Iad, R³³⁰ ishydrogen, R³³¹ is fluoro, chloro, or lower alkoxy and R³³² is fluoro,chloro, or lower alkoxy.

In a fifty-fifth aspect, compounds of Formula I having the structureaccording to the following Formula Iae are provided:

or a salt, a prodrug, a solvate, a tautomer or a stereoisomer thereof,

-   -   wherein:    -   R³³⁷ is hydrogen, fluoro, chloro, or lower alkyl optionally        substituted with one or more fluoro;    -   R³³⁸ and R³³⁹ are hydrogen and R³⁴⁰ is selected from the group        consisting of fluoro, chloro, —O—R³⁴¹, —S—R³⁴², —S(O₂)—R³⁴³, and        lower alkyl optionally substituted with one or more R³⁴⁴; or    -   R³³⁸ and R³⁴⁰ are hydrogen and R³³⁹ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³³⁹ and R³⁴⁰ are hydrogen and R³³⁸ is fluoro, chloro, lower        alkyl optionally substituted with one or more fluoro, or lower        alkoxy optionally substituted with one or more fluoro; or    -   R³³⁸ is hydrogen, R³³⁹ is fluoro, chloro, lower alkyl optionally        substituted with one or more fluoro, or lower alkoxy optionally        substituted with one or more fluoro and R³⁴⁰ is fluoro, chloro,        lower alkyl optionally substituted with one or more fluoro, or        lower alkoxy optionally substituted with one or more fluoro;    -   R³⁴¹, R³⁴² and R³⁴³ are lower alkyl optionally substituted with        one or more fluoro; and    -   R³⁴⁴ is fluoro, —OH, or lower alkoxy optionally substituted with        one or more fluoro.

In some embodiments of compounds of Formula Iae, R³³⁷ is hydrogen,chloro or lower alkyl. In one embodiment, R³³⁷ is chloro or C₁₋₃ alkyl.In one embodiment, R³³⁷ is chloro or methyl.

In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁸ and R³³⁹ are hydrogen and R³⁴⁰ isselected from the group consisting of fluoro, chloro, —O—R³⁴¹, —S—R³⁴²,—S(O₂)—R³⁴³, and lower alkyl optionally substituted with one or moreR³⁴⁴. In some embodiments of compounds of Formula Iae, further to any ofthe above embodiments of Formula Iae, R³³⁸ and R³³⁹ are hydrogen andR³⁴⁰ is selected from the group consisting of fluoro, chloro, loweralkoxy, lower alkylthio, lower alkylsulfonyl, and lower alkyl optionallysubstituted with one or more fluoro or —OH. In some embodiments ofcompounds of Formula Iae, further to any of the above embodiments ofFormula Iae, R³³⁸ and R³³⁹ are hydrogen and R³⁴⁰ is selected from thegroup consisting of fluoro, chloro, lower alkoxy, lower alkylthio, loweralkylsulfonyl, and lower alkyl.

In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁸ and R³⁴⁰ are hydrogen and R³³⁹ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁸ and R³⁴⁰ are hydrogen and R³³⁹ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁹ and R³⁴⁰ are hydrogen and R³³⁸ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁹ and R³⁴⁰ are hydrogen and R³³⁸ isfluoro, chloro, lower alkyl or lower alkoxy.

In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁸ is hydrogen, R³³⁹ is fluoro,chloro, lower alkyl optionally substituted with one or more fluoro, orlower alkoxy optionally substituted with one or more fluoro and R³⁴⁰ isfluoro, chloro, lower alkyl optionally substituted with one or morefluoro, or lower alkoxy optionally substituted with one or more fluoro.In some embodiments of compounds of Formula Iae, further to any of theabove embodiments of Formula Iae, R³³⁸ is hydrogen, R³³⁹ is fluoro,chloro, lower alkyl or lower alkoxy and R³⁴⁰ is fluoro, chloro, loweralkyl or lower alkoxy. In some embodiments of compounds of Formula Iae,further to any of the above embodiments of Formula Iae, R³³⁸ ishydrogen, R³³⁹ is fluoro, chloro, or lower alkoxy and R³⁴⁰ is fluoro,chloro, or lower alkoxy.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of those set forth in Table 1.

TABLE 1[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amine(P-3001),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopentyl-amine(P-3003),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-difluoro-cyclohexyl)-amine(P-3004),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopropyl-amine(P-3005),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cycloheptyl-amine(P-3006),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobutyl-amine(P-3007),Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-3008),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine(P-3009),(4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3010),(4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3011),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine(P-3012),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amine (P-3013),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-phenyl)-amine(P-3014),(2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3015),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-phenyl)-amine(P-3016),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-phenyl)-amine(P-3017),[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine (P-3018),[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-3019),(6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3020),(4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3021),(4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3022),(3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3023),[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-propoxy-phenyl)-amine(P-3024),(4-Ethyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3025),(4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3026),(6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3027),[5-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-3028),(5-tert-Butyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3029),(4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3030),1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol (P-3031),(5-Cyclopropyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-3032),[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine(P-3033),(4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3034),(1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3035),(1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine(P-3036),[5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-trifluoromethyl-2H-pyrazol-3-yl)-amine (P-3037),(5-Isopropoxy-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-3038),(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-3039),[2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3040),[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine(P-3041),[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine(P-3042),[2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3043),(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone (P-3044),[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3045),(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-3048),[6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3049),(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-3050),[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-3051),[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-3052),(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-3053),[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4001),[6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4002),(6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4003),(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4004),(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4005),(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4006),(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4007),(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4008),(6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4009),[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4010),(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4011),[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4012),(1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4013),(1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4014),{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methyl-pyridin-3-yl)-amine (P-4015),(6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine (P-4016),[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4017),[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4018),{6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine (P-4019),(6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4020),[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-pyridin-3-yl-amine(P-4021),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone (P-4022),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine (P-4023),[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4024),(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone (P-4025),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine (P-4026),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4027),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine (P-4028),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4029),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine (P-4030),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone (P-4031),[6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4032),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine (P-4036),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4-ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4037),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-amine (P-4038),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone (P-4039),[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4040),(6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4041),[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6,7-dihydro-5H-[1]pyrindin-3-yl)-amine (P-4042),(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6,7-dihydro-5H-[1]pyrindin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone (P-4043),(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine (P-4044),[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (P-4045),(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]methanone (P-4046),[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2-methylprop-1-enylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4047),(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4048),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(2-hydroxy-2-methyl-propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4049),[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4050),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4051),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4052),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone (P-4053),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4054),[4-(tert-butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4055),[4-[(4,4-difluorocyclohexyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4056),[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4057),[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4058),[2-chloro-6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4059),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4060),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4061),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone (P-4062),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4063),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(2-hydroxy-2-methyl-propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4064),(4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4065),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4066),[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4067),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4068),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(1-piperidyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4069),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-(4-morpholino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (P-4070),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[6-(trifluoromethyl)-3-pyridyl]methylamino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4071),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4072),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(tetrahydrofuran-2-ylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4073),[4-[(1-ethyl-4-piperidyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4074),[4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4075),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4076),[4-(1-ethylpropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4077),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(sec-butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4078),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4079),[4-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4080),[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4081),[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4082),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4083),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4084),[2-methoxy-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4085),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(6-methyl-3-pyridyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4086),[6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4087),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]methanone (P-4088),[6-[(4,4-difluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4089),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4090),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[[6-(trifluoromethyl)-3-pyridyl]amino]-3-pyridyl]methanone (P-4091),[2-fluoro-6-[[6-(trifluoromethyl)-3-pyridyl]amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4092),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4093),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4094),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4095),[4-[(4,4-difluorocyclohexyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4096),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-(4-fluorophenyl)ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4097),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4098),[4-(cyclopentylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4099),[4-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4100),[6-(cyclohexylamino)-2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4101),[6-(cyclohexylamino)-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4102),[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4103),[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4104),[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4105),[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4106),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4107),[2-fluoro-6-[(5-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4108),[2-chloro-6-(cyclohexylamino)-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4109),[2-chloro-6-(cyclohexylamino)-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4110),[4-(cyclohexylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone (P-4111),[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4112),[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone (P-4113),[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4114),[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4115),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4116),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4117),[4-(cyclopropylmethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4118),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2-methoxyethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4119),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4120),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(isobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4121),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4122),[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4123),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4124),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methanone (P-4125),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]methanone (P-4126),N-cyclopropyl-5-[[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (P-4127),5-[[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methyl]-N-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (P-4128),N-cyclopropyl-5-[[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (P-4129),5-[[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]methyl]-N-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (P-4130),5-[[6-(cyclohexylamino)-2-fluoro-3-pyridyl]methyl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (P-4131),[2-fluoro-6-[(6-methoxy-3-pyridyl)amino]-3-pyridyl]-[4-[[(1R)-1-(4-fluorophenyl)ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4132),[6-[(6-ethyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(4-fluorophenyl)ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4133),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4134),[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4135),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4136),[4-(cyclopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4137),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4138),[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4139),[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4140),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(methoxymethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4141),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4142),[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4143),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]methanone (P-4144),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4145),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4146),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4147),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4148),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4149),[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone (P-4150),[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone (P-4151),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(methoxymethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4152),[6-[(3,3-15difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4153),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone (P-4154),[6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4155),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4156),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(2-methoxyethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4157),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone (P-4158),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4159),[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone (P-4160),[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone (P-4161),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4162),[4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone (P-4163),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(methoxymethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4164),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4165),[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4166),[4-[[(1R)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone (P-4167),[4-[[(1S)-1-cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone (P-4168),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-methylpropyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4169),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy-1-methyl-propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4170),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(hydroxymethyl)propyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4171),4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one (P-4172),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4173),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4174),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydroxycyclopentyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4175),1-[3-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-1-yl]ethanone (P-4176),(2R)-2-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexanone (P-4177),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothiolan-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4178),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4179),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4180),4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]piperidin-2-one (P-4181),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4182),4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-methyl-piperidin-2-one (P-4183),[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothian-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4184),1-cyclopropyl-4-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one (P-4185),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-methylpropyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4186),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy-1-methyl-propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4187),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1-(hydroxymethyl)propyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4188),4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one (P-4189),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-hydroxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4190),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3-hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4191),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydroxycyclopentyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4192),1-[3-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-1-yl]ethanone (P-4193),(2R)-2-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexanone (P-4194),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothiolan-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4195),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2-hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4196),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4197),4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]piperidin-2-one (P-4198),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4199),4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-methyl-piperidin-2-one (P-4200),[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothian-3-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (P-4201),1-cyclopropyl-4-[[5-[6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one (P-4202); and anysalt, prodrug, solvate, tautomer, or stereoisomer thereof. In someembodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amine    (P-3001),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopentyl-amine    (P-3003),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3004),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopropyl-amine    (P-3005),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cycloheptyl-amine    (P-3006),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobutyl-amine    (P-3007),-   Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3008),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine    (P-3009),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3013), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3004),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cycloheptyl-amine    (P-3006),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3013), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   (1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3035),-   (1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3036),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4011),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4012),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4013),-   (1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4014),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4036),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4037), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   (4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3010),-   (4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3011),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine    (P-3012),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-phenyl)-amine    (P-3014),-   (2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3015),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-phenyl)-amine    (P-3016),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-phenyl)-amine    (P-3017),-   (4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3021),-   (4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3022),-   (3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3023),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-propoxy-phenyl)-amine    (P-3024),-   (4-Ethyl-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3025),-   (4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3026),-   (4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3030),-   1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol    (P-3031),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine    (P-3033),-   (4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3034), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   (4-Fluoro-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3010),-   (4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3011),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine    (P-3012),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-phenyl)-amine    (P-3014),-   (4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3021),-   (4-Ethyl-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3025),-   (4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3026),-   (4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3030),-   1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol    (P-3031),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine    (P-3033), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine    (P-3018),-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-3019),-   (6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3020),-   (6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3027),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3039),-   [2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3040),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3045),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4001),-   [6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4002),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4005),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4006),-   (6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4008),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4018),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine    (P-4019),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4022),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4023),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4024),-   (4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4025),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine    (P-4026),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4027),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4032), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine    (P-3018),-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-3019),-   (6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3020),-   (6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3027),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3039),-   [2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3040),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3045),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4001),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4005),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4006),-   (6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4008),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4018),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine    (P-4019),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4022),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4023),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine    (P-4026),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4027),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4032), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3041),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3042),-   [2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3043),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-3044),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3048),-   [6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3049),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3050),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3051),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3052),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3053),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4004),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4007),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4009),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4010),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methyl-pyridin-3-yl)-amine    (P-4015),-   (6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4016),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4017),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine    (P-4028),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4029),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4030),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4031),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4040),-   (6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4041),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6,7-dihydro-5H-[1]pyrindin-3-yl)-amine    (P-4042),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6,7-dihydro-5H-[1]pyrindin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4043),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4044),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4045), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3041),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3042),-   [2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3043),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-3044),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3048),-   [6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3049),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3050),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3051),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3052),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3053),-   (6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4004),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4007),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4009),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4010),-   (6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4016),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4017),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine    (P-4028),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4029),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4030),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4031),-   [6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4040),-   (6-Cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4041), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   (6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4003),-   (6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4020),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-pyridin-3-yl-amine    (P-4021),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-amine    (P-4038),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4039), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-3019),-   (6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3020),-   (4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3021),-   [2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3043),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-3044),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3045),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3048),-   [6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3049),-   (6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4008),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4009),-   (6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4016),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4018),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine    (P-4019),-   (6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4020),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4023),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine    (P-4026),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine    (P-4028),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4029),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4030), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-3019),-   (6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3020),-   (4-Methoxy-phenyl)-[5-(5-methyl-1-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3021),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3048),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4009),-   (6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4016),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4018),-   (6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4020),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine    (P-4026),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine    (P-4028),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4029), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3043),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-3044),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3045),-   [6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3049),-   (6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4008),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine    (P-4019),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4023),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4030), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3004),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3013),-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3041),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3042),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4010),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4011),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4012),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4013),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4036), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt.

In one embodiment of compounds of Formula I, the compound is selectedfrom the group consisting of:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cycloheptyl-amine    (P-3006),-   (4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3010),-   (4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3011),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine    (P-3012),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-phenyl)-amine    (P-3014),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine    (P-3018),-   (4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3026),-   (6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3027),-   (1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3036),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3039),-   (1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4014),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4017), and    any salt, prodrug, solvate, tautomer, or stereoisomer thereof. In    some embodiments, the salt is a pharmaceutically acceptable salt. In    some embodiments, the invention provides a compound as set forth in    Table 7 and any salt, solvate, prodrug, stereoisomer, or tautomer    thereof. In some embodiments, the salt is a pharmaceutically    acceptable salt.

In reference to compounds herein, unless clearly indicated to thecontrary, specification of a compound or group of compounds includessalts of such compound(s) (including pharmaceutically acceptable salts),formulations of such compound(s) (including pharmaceutically acceptableformulations), conjugates thereof, derivatives thereof, forms thereof,prodrugs thereof, and all stereoisomers thereof. In reference tocompositions, kits, methods of use, etc. of compounds of Formula Idescribed herein, it is understood (unless indicated otherwise) that acompound of Formula I includes all sub-embodiments thereof (Includingany sub-generic Formulae Ia through Iae).

In a fifty-sixth aspect, a compound of Formula I is an inhibitor of Fmskinase and has an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Fms kinase activity assay. Insome embodiments, the compound is selective relative to other proteinkinases, such that the ratio of IC₅₀ for another kinase assessedcomparably, divided by the IC₅₀ for Fms kinase is >20, also >30,also >40, also >50, also >60, also >70, also >80, also >90, also >100,wherein the other protein kinase includes, but is not limited to CSK,Insulin receptor kinase, AMPK, PDGFR or VEGFR. In some embodiments, thecompound is selective relative to Kit protein kinase, such that theratio of IC₅₀ for Kit kinase assessed comparably, divided by the IC₅₀for Fms kinase is >20, also >30, also >40, also >50, also >60, also >70,also >80, also >90, also >100.

In fifty-seventh aspect, a compound of Formula I is a Fms selectiveinhibitor, i.e. will selectively inhibit Fms kinase relative to Kitkinase. In some embodiments the compound will have an IC₅₀ of less than500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than 10nM, less than 5 nM, or less than 1 nM as determined in a generallyaccepted Fms kinase activity assay and when determined in a comparablegenerally accepted Kit kinase activity assay will have a ratio of IC₅₀for Kit kinase divided by the IC₅₀ for Fms kinase of >20, also >30,also >40, also >50, also >60, also >70, also >80, also >90, also >100.In some embodiments, the compound is also selective relative to proteinkinases other than Kit, such that the ratio of IC₅₀ for another kinaseassessed comparably, divided by the IC₅₀ for Fms kinase is >20,also >30, also >40, also >50, also >60, also >70, also >80, also >90,also >100, wherein the other protein kinase includes, but is not limitedto Flt-3, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. In oneembodiment, the Fms selective inhibitor does not effectively cross theblood brain barrier. In one embodiment, the Fms selective inhibitor doeseffectively cross the blood brain barrier.

In a fifty-eighth aspect, a compound of Formula I is a dual Fms/Kitinhibitor, i.e. will be approximately equipotent with respect toinhibition of Fms kinase and Kit kinase. In some embodiments thecompound will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a generally accepted Fms kinase activityassay and will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a comparable generally accepted Kit kinaseactivity assay, wherein the ratio of IC₅₀ for Kit kinase divided by theIC₅₀ for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1, also5 to 0.2. In some embodiments, the compound is selective relative toother protein kinases, such that the ratio of IC₅₀ for another kinaseassessed comparably, divided by the IC₅₀ for Fms kinase (and/or Kitkinase) is >20, also >30, also >40, also >50, also >60, also >70,also >80, also >90, also >100, wherein the other protein kinaseincludes, but is not limited to CSK, Insulin receptor kinase, AMPK,PDGFR or VEGFR.

In a fifty-ninth aspect, a compound of Formula I is a dual Fms/Flt-3inhibitor, i.e. will be approximately equipotent with respect toinhibition of Fms kinase and Flt-3 kinase. In some embodiments thecompound will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a generally accepted Fms kinase activityassay and will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a comparable generally accepted Flt-3 kinaseactivity assay, wherein the ratio of IC₅₀ for Flt-3 kinase divided bythe IC₅₀ for Fms kinase is in the range of 20 to 0.05, also 10 to 0.1,also 5 to 0.2. In some embodiments, the compound is selective relativeto other protein kinases, such that the ratio of IC₅₀ for another kinaseassessed comparably, divided by the IC₅₀ for Fms kinase (and/or Flt3kinase) is >20, also >30, also >40, also >50, also >60, also >70,also >80, also >90, also >100, wherein the other protein kinaseincludes, but is not limited to CSK, Insulin receptor kinase, AMPK,PDGFR or VEGFR. In some embodiments, the dual Fms/Flt-3 inhibitor isselective with respect to Kit. In some embodiments, the dual Fms/Flt-3inhibitor also inhibits Kit.

In a sixtieth aspect, a compound of Formula I is a dual Fms/Trkinhibitor, i.e. will be approximately equipotent with respect toinhibition of Fms kinase and Trk kinase. In some embodiments thecompound will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a generally accepted Fms kinase activityassay and will have an IC₅₀ of less than 500 nm, less than 100 nM, lessthan 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or lessthan 1 nM as determined in a comparable generally accepted Trk kinaseactivity assay (including any one or more of TrkA, TrkB, and TrkC),wherein the ratio of IC₅₀ for Trk kinase (at least one of TrkA, TrkB,and TrkC) divided by the IC₅₀ for Fms kinase is in the range of 20 to0.05, also 10 to 0.1, also 5 to 0.2. In some embodiments, the compoundis selective relative to other protein kinases, such that the ratio ofIC₅₀ for another kinase assessed comparably, divided by the IC₅₀ for Fmskinase (and/or Trk kinase) is >20, also >30, also >40, also >50,also >60, also >70, also >80, also >90, also >100, wherein the otherprotein kinase includes, but is not limited to CSK, Insulin receptorkinase, AMPK, PDGFR or VEGFR. In some embodiments, the dual Fms/Trkinhibitor is selective with respect to Kit. In some embodiments, thedual Fms/Trk inhibitor also inhibits Kit.

Further to any of the above mentioned aspects and embodiments, acompound of Formula I will also inhibit the effects of a mutation of thekinase, including, but not limited to, a mutation that is related to adisease state, such as a cancer.

In a sixty-first aspect, compositions are provided that include atherapeutically effective amount of any one or more compound(s) ofFormula I and at least one pharmaceutically acceptable carrier,excipient, and/or diluent, including combinations of any two or morecompounds of Formula I. The composition can further include a pluralityof different pharmacologically active compounds, which can include aplurality of compounds of Formula I. In certain embodiments, thecomposition can include any one or more compound(s) of Formula I alongwith one or more compounds that are therapeutically effective for thesame disease indication. In one aspect, the composition includes any oneor more compound(s) of Formula I along with one or more compounds thatare therapeutically effective for the same disease indication, whereinthe compounds have a synergistic effect on the disease indication. Inone embodiment, the composition includes any one or more compound(s) ofFormula I effective in treating a cancer and one or more other compoundsthat are effective in treating the same cancer, further wherein thecompounds are synergistically effective in treating the cancer.

In a sixty-second aspect, methods are provided for treating a disease orcondition related to any one or more of Fms protein kinase, Kit proteinkinase, Flt3 protein kinase, and Trk protein kinase in an animal subjectin need thereof, wherein the method involves administering to thesubject an effective amount of any one or more compound(s) of Formula Ior a composition comprising any one or more compound(s) of Formula I. Incertain embodiments, the method involves administering to the subject aneffective amount of a compound of Formula I or a composition comprisinga compound of Formula I in combination with one or more other therapiesfor the disease or condition.

In a sixty-third aspect, methods are provided for treating a disease orcondition related to Fms protein kinase in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I. Incertain embodiments, the method involves administering to the subject aneffective amount of a compound of Formula I or a composition comprisinga compound of Formula I in combination with one or more other therapiesfor the disease or condition.

In a sixty-fourth aspect, methods are provided for treating a disease orcondition related to Trk protein kinase in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I. Incertain embodiments, the method involves administering to the subject aneffective amount of a compound of Formula I or a composition comprisinga compound of Formula I in combination with one or more other therapiesfor the disease or condition.

In a sixty-fifth aspect, methods are provided for treating a disease orcondition related to Kit protein kinase in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I. Incertain embodiments, the method involves administering to the subject aneffective amount of a compound of Formula I or a composition comprisinga compound of Formula I in combination with one or more other therapiesfor the disease or condition.

In a sixty-sixth aspect, methods are provided for treating a disease orcondition related to Flt3 protein kinase in an animal subject in needthereof, wherein the method involves administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I. Incertain embodiments, the method involves administering to the subject aneffective amount of a compound of Formula I or a composition comprisinga compound of Formula I in combination with one or more other therapiesfor the disease or condition.

In a sixty-seventh aspect, methods are provided for treating a diseaseor condition related to Fms protein kinase and Kit protein kinase in ananimal subject in need thereof, wherein the method involvesadministering to the subject an effective amount of any one or more dualFms/Kit inhibitor(s) of Formula I or a composition comprising any one ormore dual Fms/Kit inhibitor(s) of Formula I. In certain embodiments, themethod involves administering to the subject an effective amount of adual Fms/Kit inhibitor of Formula I or a composition comprising a dualFms/Kit inhibitor of Formula I in combination with one or more othertherapies for the disease or condition.

In a sixty-eighth aspect, methods are provided for treating a disease orcondition related to Fms protein kinase and Flt-3 protein kinase in ananimal subject in need thereof, wherein the method involvesadministering to the subject an effective amount of any one or more dualFms/Flt-3 inhibitor(s) of Formula I or a composition comprising any oneor more dual Fms/Flt-3 inhibitor(s) of Formula I. In certainembodiments, the method involves administering to the subject aneffective amount of a dual Fms/Flt-3 inhibitor of Formula I or acomposition comprising a dual Fms/Flt-3 inhibitor of Formula I incombination with one or more other therapies for the disease orcondition.

In a sixty-ninth aspect, methods are provided for treating a disease orcondition related to Fms protein kinase and Trk protein kinase in ananimal subject in need thereof, wherein the method involvesadministering to the subject an effective amount of any one or more dualFms/Trk inhibitor(s) of Formula I or a composition comprising any one ormore dual Fms/Trk inhibitor(s) of Formula I. In certain embodiments, themethod involves administering to the subject an effective amount of adual Fms/Trk inhibitor of Formula I or a composition comprising a dualFms/Trk inhibitor of Formula I in combination with one or more othertherapies for the disease or condition.

In a seventieth aspect, the invention provides a method of treating acancer in a subject in need thereof by administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I, incombination with one or more other therapies or medical procedureseffective in treating the cancer. Other therapies or medical proceduresinclude suitable anticancer therapy (e.g. drug therapy, vaccine therapy,gene therapy, photodynamic therapy) or medical procedure (e.g. surgery,radiation treatment, hyperthermia heating, bone marrow or stem celltransplant). In one embodiment, the one or more suitable anticancertherapies or medical procedures is selected from treatment with achemotherapeutic agent (e.g. chemotherapeutic drug), radiation treatment(e.g. x-ray, □-ray, or electron, proton, neutron, or □ particle beam),hyperthermia heating (e.g. microwave, ultrasound, radiofrequencyablation), Vaccine therapy (e.g. AFP gene hepatocellular carcinomavaccine, AFP adenoviral vector vaccine, AG-858, allogeneicGM-CSF-secretion breast cancer vaccine, dendritic cell peptidevaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encodingMDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy(e.g. aminolevulinic acid, motexafin lutetium), surgery, or bone marrowand stem cell transplantation.

In a seventy-first aspect, the invention provides a method of treating acancer in a subject in need thereof by administering to the subject aneffective amount of any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I, incombination with one or more suitable chemotherapeutic agents. In oneembodiment, the one or more suitable chemotherapeutic agents is selectedfrom an alkylating agent, including, but not limited to, adozelesin,altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone,carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide,dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam,ifosfamide, improsulfan, irofulven, lomustine, mannosulfan,mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine,oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine,satraplatin, semustine, streptozocin, temozolomide, thiotepa,treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate,trofosphamide, and uramustine; an antibiotic, including, but not limitedto, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin,doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin,neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, andzorubicin; an antimetabolite, including, but not limited to,aminopterin, azacitidine, azathioprine, capecitabine, cladribine,clofarabine, cytarabine, decitabine, floxuridine, fludarabine,5-fluorouracil, 2′-F-ara-deoxyuridine, gemcitabine, hydroxyurea,mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate,azathioprine, raltitrexed, tegafur-uracil, thioguanine, trimethoprim,trimetrexate, and vidarabine; an immunotherapy, including, but notlimited to, alemtuzumab, bevacizumab, cetuximab, denileukin diftitox,galiximab, gemtuzumab, ofatumumab, panitumumab, pertuzumab, rituximab,tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan, ipilimumab, andtremelimumab; a hormone or hormone antagonist, including, but notlimited to, anastrozole, androgens, bicalutamide, buserelin, Degarelix,diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin,idoxifene, letrozole, leuprolide, megestrol, nilutamide, raloxifene,tamoxifen, 4-hydroxytamoxifen, toremifene, and triptorelin; a taxane,including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel,ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; a retinoid,including, but not limited to, alitretinoin, bexarotene, fenretinide,isotretinoin, and tretinoin; an alkaloid, including, but not limited to,demecolcine, homoharringtonine, vinblastine, vincristine, vindesine,vinflunine, and vinorelbine; an antiangiogenic agent, including, but notlimited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol,lenalidomide, and thalidomide; a topoisomerase inhibitor, including, butnot limited to, amsacrine, belotecan, edotecarin, etoposide, etoposidephosphate, exatecan, irinotecan (also active metabolite SN-38(7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone,pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; akinase inhibitor, including, but not limited to, axitinib (AG 013736),dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinibmesylate, lapatinib, motesanib diphosphate (AMG 706), nilotinib(AMN107), pazopanib, seliciclib, sorafenib, sunitinib malate, AEE-788,BMS-599626, UCN-01 (7-hydroxystaurosporine), PLX4032, vatalanib, mTORinhibitors (e.g. temsirolimus, everolimus, deforolimus, rapamycin), PI3Kinhibitors (e.g. BEZ235, GDC-0941, XL147, XL765, CAL-101, PX-866,BGT226, GSK1059615), Cdk4 inhibitors (e.g. PD-332991, AG-024322), Aktinhibitors (e.g. GSK2110183, SR13668), MEK inhibitors (e.g. PD0325901,AZD8330, GSK1120212, RO4987655, RDEA119, XL518); a targeted signaltransduction inhibitor including, but not limited to bortezomib, andgeldanamycin; a biological response modifier, including, but not limitedto, imiquimod, interferon-□, and interleukin-2; and otherchemotherapeutics, including, but not limited to 3-AP(3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan,aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide,elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine,masoprocol, mitoguanazone, oblimersen, sulindac, testolactone,tiazofurin, COX-2 inhibitors (e.g. celecoxib, rofecoxib, valdecoxib,lumiracoxib, etoricoxib), Hsp90 inhibitors (e.g. tanespimycin) andfarnesyltransferase inhibitors (e.g. tipifarnib).

In a seventy-second aspect, the invention provides kits that include anyone or more compound(s) of Formula I or a composition comprising any oneor more compound(s) of Formula I. In some embodiments, the compound orcomposition is packaged, e.g., in a vial, bottle, flask, which may befurther packaged, e.g., within a box, envelope, or bag; the compound orcomposition is approved by the U.S. Food and Drug Administration orsimilar regulatory agency for administration to a mammal, e.g., a human;the compound or composition is approved for administration to a mammal,e.g., a human, for a protein kinase mediated disease or condition; theinvention kit includes written instructions for use and/or otherindication that the compound or composition is suitable or approved foradministration to a mammal, e.g., a human, for a protein kinase-mediateddisease or condition; and the compound or composition is packaged inunit dose or single dose form, e.g., single dose pills, capsules, or thelike.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition with any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I, theinvention provides methods for treating a disease or condition relatedto Kit in an animal subject in need thereof (e.g. a mammal such as ahuman, other primates, sports animals, animals of commercial interestsuch as cattle, farm animals such as horses, or pets such as dogs andcats), e.g., a disease or condition characterized by abnormal Kitactivity (e.g. kinase activity). In some embodiments invention methodsmay involve administering to the subject suffering from or at risk of adisease or condition related to Kit an effective amount of any one ormore compound(s) of Formula I or a composition comprising any one ormore compound(s) of Formula I. In one embodiment, the disease related toKit is selected from the group consisting of malignancies, including,but not limited to, mast cell tumors, small cell lung cancer, non-smallcell lung cancer (NSCLC), testicular cancer, pancreatic cancer, breastcancer, prostate cancer, merkel cell carcinoma, carcinomas of the femalegenital tract, sarcomas of neuroectodermal origin, colorectal carcinoma,carcinoma in situ, gastrointestinal stromal tumors (GISTs), multiplemyeloma, tumor angiogenesis, brain metastases, glioblastoma,astrocytoma, neuroblastoma, neurofibromatosis (including Schwann cellneoplasia associated with neurofibromatosis), acute myeloid leukemia,acute lymphocytic leukemia, chronic myeloid leukemia, mastocytosis,melanoma, and canine mast cell tumors; cardiovascular disease, includingbut not limited to atherosclerosis, cardiomyopathy, heart failure,pulmonary arterial hypertension and pulmonary fibrosis; inflammatory andautoimmune indications, including, but not limited to, allergy,anaphylaxis, asthma, rheumatoid arthritis, allergic rhinitis, multiplesclerosis, inflammatory bowel disease, transplant rejection,hypereosinophilia, urticaria and dermatitis; gastrointestinalindications, including but not limited to gastroesophageal refluxdisease (GERD), esophagitis, and gastrointestinal tract ulcers;ophthalmic indications, including but not limited to uveitis andretinitis; and neurologic indications, including but not limited tomigraine.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition with any one or more compound(s) of Formula I or acomposition comprising any one or more compound(s) of Formula I, theinvention provides methods for treating a disease or condition relatedto Fms in an animal subject in need thereof (e.g. a mammal such as ahuman, other primates, sports animals, animals of commercial interestsuch as cattle, farm animals such as horses, or pets such as dogs andcats), e.g., a disease or condition characterized by abnormal Fmsactivity (e.g. kinase activity). In some embodiments, invention methodsmay involve administering to the subject suffering from or at risk of adisease or condition related to Fms an effective amount of any one ormore compound(s) of Formula I or a composition comprising any one ormore compound(s) of Formula I. In one embodiment, the disease related toFms is selected from the group consisting of inflammatory and autoimmuneindications, including, but not limited to, rheumatoid arthritis,osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosingspondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenileidiopathic arthritis, polymyalgia rheumatica, Sjogren's disease,Langerhan's cell histiocytosis (LCH), Still's disease, inflammatorybowel disease, ulcerative colitis, Crohn's disease, systemic lupuserythematosis (SLE), immune thrombocytopenic purpura (ITP),myelopreparation for autologous transplantation, transplant rejection,chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki'sDisease, hemophagocytic syndrome (macrophage activation syndrome),multicentric reticulohistiocytosis, and atherosclerosis; metabolicdisorders, including, but not limited to, Type I diabetes, Type IIdiabetes, insulin resistance, hyperglycemia, obesity, and lipolysis;disorders of bone structure, mineralization and bone formation andresorption, including, but not limited to, osteoporosis, osteodystrophy,increased risk of fracture, Paget's disease, hypercalcemia,infection-mediated osteolysis (e.g. osteomyelitis), and peri-prostheticor wear-debris-mediated osteolysis; kidney and genitourinary diseases,including, but not limited to, endometriosis, nephritis (e.g.glomerulonephritis, interstitial nephritis, Lupus nephritis), tubularnecrosis, diabetes-associated renal complications (e.g. diabeticnephropathy), and renal hypertrophy; disorders of the nervous system,including, but not limited to, demyelinating disorders (e.g. multiplesclerosis, Charcot Marie Tooth syndrome), amyotrophic lateral sclerosis(ALS), myasthenia gravis, chronic demyelinating polyneuropathy, otherdemyelinating disorders, stroke, Alzheimer's disease and Parkinson'sdisease; pain, including, but not limited to, chronic pain, acute pain,inflammatory pain, neuropathic pain, bone pain; malignancies, including,but not limited to, multiple myeloma, acute myeloid leukemia (AML),chronic myeloid leukemia (CIVIL), lung cancer, pancreatic cancer,prostate cancer, breast cancer, ovarian cancer, neuroblastoma, sarcoma,osteosarcoma, giant cell tumors, (e.g. giant cell tumor of bone, giantcell tumor of tendon sheath (TGCT)), pigmented villonodular synovitis(PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma,other tumors of the central nervous system, brain metastases, osteolyticbone metastases, metastasis of tumors to other tissues, and otherchronic myeloproliferative diseases such as myelofibrosis; vasculitis,including but not limited to collagen vascular disease, polyarteritisnodosa, Behcet's disease, sarcoidosis, familiar Mediterranean fever,Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis,Takayasu's arteritis; ophthalmic indications, including but not limitedto uveitis, scleritis, retinitis, age related macular degeneration,choroidal neovascularization, diabetic retinopathy; inherited disorders,including but not limited to cherubism, neurofibromatosis; infectiousdisease indications, including but not limited to infections associatedwith human immunodeficiency virus, hepatitis B virus, hepatitis C virus,human granulocytic anaplasmosis; lysosomal storage disorders, includingbut not limited to Gaucher's disease, Fabry's disease, Niemann-Pickdisease; gastrointestinal indications, including but not limited toliver cirrhosis; pulmonary indications, including but not limited topulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke-or toxin-induced); global ischemia, and surgical indications, includingbut not limited to (cardiopulmonary) bypass surgery, vascular surgery,and vascular grafts.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition with the any one or more compound(s) of Formula Ior a composition comprising any one or more compound(s) of Formula I,the invention provides methods for treating a disease or conditionrelated to Flt-3 in an animal subject in need thereof (e.g. a mammalsuch as a human, other primates, sports animals, animals of commercialinterest such as cattle, farm animals such as horses, or pets such asdogs and cats), e.g., a disease or condition characterized by abnormalFlt-3 activity (e.g. kinase activity). In some embodiments, inventionmethods may involve administering to the subject suffering from or atrisk of a disease or condition related to Flt-3 an effective amount ofany one or more compound(s) of Formula I or a composition comprising anyone or more compound(s) of Formula I. In one embodiment, the diseaserelated to Flt-3 is selected from the group consisting of malignancies,including, but not limited to, glioma, glioblastoma, brain metastases,lung cancer, breast cancer, colorectal cancer, prostate cancer, gastriccancer, esophageal cancer, pancreatic cancer, ovarian cancer,non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, acutelymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemiawith trilineage myelodysplasia, acute promyelocytic leukemia, chroniclymphocytic leukemia, chronic myeloid leukemia, chronic neutrophilicleukemia, acute undifferentiated leukemia, anaplastic large-celllymphoma, prolymphocyte leukemia, juvenile myelomonocyctic leukemia,adult T-cell acute lymphocytic leukemia, T-cell type acute lymphocyticleukemia, B-cell type acute lymphocytic leukemia, mixed lineageleukemia, multiple myeloma, chronic myelocytic leukemia, acutelymphoblastic leukemia, acute myeloblastic leukemia, chronicmyelomonocytic leukemia; other diseases including psoriasis, atopicdermatitis, axonal degeneration, acute transverse myelitis, amyotrophiclateral sclerosis, infantile spinal muscular atrophy, juvenile spinalmuscular atrophy, Creutzfeldt-Jakob disease, subacute sclerosingpanencephalitis, organ rejection, bone marrow transplant rejection,non-myeloablative bone marrow transplant rejection, ankylosingspondylitis, aplastic anemia, Behcet's disease, graft-versus-hostdisease, Graves' disease, autoimmune hemolytic anemia, Wegener'sgranulomatosis, hyper IgE syndrome, idiopathic thrombocytopenia purpura,Myasthenia gravis, type 1 diabetes mellitus, rheumatoid arthritis,Crohn's disease, multiple sclerosis, systemic lupus erythematosus,myelodysplastic syndrome, thrombocythemia, essential thrombocytosis,angiogenic myeloid metaplasia, myelofibrosis, myelofibrosis with myeloidmetaplasia, chronic idiopathic myelofibrosis, polycythemia vera, anemia,leukopenia, neutropenia, thrombocytopenia, granulocytopenia, andpancytopenia.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition with the any one or more compound(s) of Formula Ior a composition comprising any one or more compound(s) of Formula I,the invention provides methods for treating a disease or conditionrelated to Trk in an animal subject in need thereof (e.g. a mammal suchas a human, other primates, sports animals, animals of commercialinterest such as cattle, farm animals such as horses, or pets such asdogs and cats), e.g., a disease or condition characterized by abnormalTrk activity (e.g. kinase activity). In some embodiments, inventionmethods may involve administering to the subject suffering from or atrisk of a disease or condition related to Trk an effective amount of anyone or more compound(s) of Formula I or a composition comprising any oneor more compound(s) of Formula I. In one embodiment, the disease relatedto Trk is selected from the group consisting of malignancies, including,but not limited to, prostate cancer, small cell lung cancer, non-smallcell lung cancer, Wilms tumors, mesoblastic nephroma, infantilefibrosarcoma, neuroblastoma, brain cancer, squamous cell cancer, bladdercancer, gastric cancer, pancreatic cancer, breast cancer, head and neckcancer, esophageal cancer, colorectal cancer, renal cancer,hepatocellular cancer, ovarian cancer, gynecological cancer, thyroidcancer, cervical cancer, ewings tumor, tumors of the central andperipheral nervous system, melanoma, multiple myeloma, acute myelogenousleukemia, and myeloid leukemia; neuropathies, including, but not limitedto, stroke, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, transverse myelitis, and encephalitis; pain, including, but notlimited to, chronic pain, acute pain, inflammatory pain, neuropathicpain, and pain associated with cancer, surgery, or bone fracture;bone-related diseases, including, but not limited to, metastatic bonedisease, treatment-induced bone loss, osteoporosis, rheumatoidarthritis, ankylosing spondylitis, Paget's disease, and periodontaldisease; other diseases, including, but not limited to, asthma,arthritis, diabetic retinopathy, macular degeneration, psoriasis, acuteand chronic inflammation, Kaposi's sarcoma, haemangioma, acute andchronic nephropathies, atheroma, atherosclerosis, arterial restenosis,fibrosarcoma, osteosarcoma, panic disorder, and infectious disease (e.g.Typanosoma cruzi infection (Chagas disease)).

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more compound(s) of Formula I or a compositioncomprising any one or more compound(s) of Formula I to a subject in needthereof suffering from or at risk of a disease or condition selectedfrom the group consisting of rheumatoid arthritis, osteoarthritis,osteoporosis, peri-prosthetic osteolysis, systemic sclerosis,demyelinating disorders, multiple sclerosis, Charcot Marie Toothsyndrome, amyotrophic lateral sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, ulcerative colitis, Crohn'sdisease, immune thrombocytopenic purpura, atherosclerosis, systemiclupus erythematosis, myelopreparation for autologous transplantation,transplant rejection, glomerulonephritis, interstitial nephritis, Lupusnephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy,type I diabetes, acute pain, inflammatory pain, neuropathic pain, acutemyeloid leukemia, melanoma, multiple myeloma, breast cancer, prostatecancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas,glioblastomas, neurofibromatosis, osteolytic bone metastases, brainmetastases, gastrointestinal stromal tumors, and giant cell tumors.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more compound(s) of Formula I or a compositioncomprising any one or more compound(s) of Formula I to a subject in needthereof suffering from or at risk of a disease or condition selectedfrom the group consisting of rheumatoid arthritis, osteoarthritis,osteoporosis, peri-prosthetic osteolysis, multiple sclerosis,Alzheimer's disease, Parkinson's disease, global ischemia, renalhypertrophy, acute myeloid leukemia, melanoma, multiple myeloma, breastcancer, prostate cancer, pancreatic cancer, glioblastoma,neurofibromatosis, brain metastases, and gastrointestinal stromaltumors.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more Kit inhibitor(s) of Formula I or a compositioncomprising any one or more Kit inhibitor(s) of Formula I to a subject inneed thereof suffering from or at risk of a disease or conditionselected from the group consisting of rheumatoid arthritis,gastrointestinal stromal tumors, melanoma and neurofibromatosis.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more Fms selective inhibitor(s) of Formula I or acomposition comprising any one or more Fms selective inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of multiplesclerosis, Alzheimer's disease, Parkinson's disease, global ischemia,rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prostheticosteolysis, glomerulonephritis, interstitial nephritis, Lupus nephritis,diabetic nephropathy, and renal hypertrophy.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more Fms selective inhibitor(s) of Formula I or acomposition comprising any one or more Fms selective inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of multiplesclerosis, Alzheimer's disease, Parkinson's disease, and globalischemia, wherein the one or more Fms selective inhibitor(s) doeseffectively cross the blood brain barrier.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more Fms selective inhibitor(s) of Formula I or acomposition comprising any one or more Fms selective inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of rheumatoidarthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis,glomerulonephritis, interstitial nephritis, Lupus nephritis, diabeticnephropathy, and renal hypertrophy, wherein the one or more Fmsselective inhibitor(s) does not effectively cross the blood brainbarrier.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more dual Fms/Kit inhibitor(s) of Formula I or acomposition comprising any one or more dual Fms/Kit inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of breastcancer, prostate cancer, multiple myeloma, melanoma, acute myeloidleukemia, glioblastoma, brain metastases, neurofibromatosis,gastrointestinal stromal tumors, rheumatoid arthritis, and multiplesclerosis.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more dual Fms/Flt-3 inhibitor(s) of Formula I or acomposition comprising any one or more dual Fms/Flt-3 inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of breastcancer, prostate cancer, multiple myeloma, melanoma, acute myeloidleukemia, glioblastoma, brain metastases, neurofibromatosis,gastrointestinal stromal tumors, rheumatoid arthritis, and multiplesclerosis, preferably wherein the disease is acute myeloid leukemia.

In aspects and embodiments involving treatment or prophylaxis of adisease or condition, methods may involve administering an effectiveamount of any one or more dual Fms/Trk inhibitor(s) of Formula I or acomposition comprising any one or more dual Fms/Trk inhibitor(s) ofFormula I to a subject in need thereof suffering from or at risk of adisease or condition selected from the group consisting of pancreaticcancer, prostate cancer, and multiple myeloma.

In a seventy-third aspect, any one or more compound(s) of Formula I canbe used in the preparation of a medicament for the treatment of adisease or condition related to Kit selected from the group consistingof malignancies, including, but not limited to, mast cell tumors, smallcell lung cancer, non-small cell lung cancer (NSCLC), testicular cancer,pancreatic cancer, breast cancer, prostate cancer, merkel cellcarcinoma, carcinomas of the female genital tract, sarcomas ofneuroectodermal origin, colorectal carcinoma, carcinoma in situ,gastrointestinal stromal tumors (GISTs), multiple myeloma, tumorangiogenesis, brain metastases, glioblastoma, astrocytoma,neuroblastoma, neurofibromatosis (including Schwann cell neoplasiaassociated with neurofibromatosis), acute myeloid leukemia, acutelymphocytic leukemia, chronic myeloid leukemia, mastocytosis, melanoma,and canine mast cell tumors; cardiovascular disease, including but notlimited to atherosclerosis, cardiomyopathy, heart failure, pulmonaryarterial hypertension and pulmonary fibrosis; inflammatory andautoimmune indications, including, but not limited to, allergy,anaphylaxis, asthma, rheumatoid arthritis, allergic rhinitis, multiplesclerosis, inflammatory bowel disease, transplant rejection,hypereosinophilia, urticaria and dermatitis; gastrointestinalindications, including but not limited to gastroesophageal refluxdisease (GERD), esophagitis, and gastrointestinal tract ulcers;ophthalmic indications, including but not limited to uveitis andretinitis; and neurologic indications, including but not limited tomigraine.

In a seventy-fourth aspect, any one or more compound(s) of Formula I canbe used in the preparation of a medicament for the treatment of adisease or condition related to Fms selected from the group consistingof inflammatory and autoimmune indications, including, but not limitedto, rheumatoid arthritis, osteoarthritis, psoriatic arthritis,psoriasis, dermatitis, ankylosing spondylitis, polymyositis,dermatomyositis, systemic sclerosis, juvenile idiopathic arthritis,polymyalgia rheumatica, Sjogren's disease, Langerhan's cellhistiocytosis (LCH), Still's disease, inflammatory bowel disease,ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE),immune thrombocytopenic purpura (ITP), myelopreparation for autologoustransplantation, transplant rejection, chronic obstructive pulmonarydisease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome(macrophage activation syndrome), multicentric reticulohistiocytosis,and atherosclerosis; metabolic disorders, including, but not limited to,Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia,obesity, and lipolysis; disorders of bone structure, mineralization andbone formation and resorption, including, but not limited to,osteoporosis, osteodystrophy, increased risk of fracture, Paget'sdisease, hypercalcemia, infection-mediated osteolysis (e.g.osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis;kidney and genitourinary diseases, including, but not limited to,endometriosis, nephritis (e.g. glomerulonephritis, interstitialnephritis, Lupus nephritis), tubular necrosis, diabetes-associated renalcomplications (e.g. diabetic nephropathy), and renal hypertrophy;disorders of the nervous system, including, but not limited to,demyelinating disorders (e.g. multiple sclerosis, Charcot Marie Toothsyndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis,chronic demyelinating polyneuropathy, other demyelinating disorders,stroke, Alzheimer's disease and Parkinson's disease; pain, including,but not limited to, chronic pain, acute pain, inflammatory pain,neuropathic pain, bone pain; malignancies, including, but not limitedto, multiple myeloma, acute myeloid leukemia (AML), chronic myeloidleukemia (CIVIL), lung cancer, pancreatic cancer, prostate cancer,breast cancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma,giant cell tumors, (e.g. giant cell tumor of bone, giant cell tumor oftendon sheath (TGCT)), pigmented villonodular synovitis (PVNS), tumorangiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors ofthe central nervous system, brain metastases, osteolytic bonemetastases, metastasis of tumors to other tissues, and other chronicmyeloproliferative diseases such as myelofibrosis; vasculitis, includingbut not limited to collagen vascular disease, polyarteritis nodosa,Behcet's disease, sarcoidosis, familiar Mediterranean fever,Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis,Takayasu's arteritis; ophthalmic indications, including but not limitedto uveitis, scleritis, retinitis, age related macular degeneration,choroidal neovascularization, diabetic retinopathy; inherited disorders,including but not limited to cherubism, neurofibromatosis; infectiousdisease indications, including but not limited to infections associatedwith human immunodeficiency virus, hepatitis B virus, hepatitis C virus,human granulocytic anaplasmosis; lysosomal storage disorders, includingbut not limited to Gaucher's disease, Fabry's disease, Niemann-Pickdisease; gastrointestinal indications, including but not limited toliver cirrhosis; pulmonary indications, including but not limited topulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke-or toxin-induced); global ischemia, and surgical indications, includingbut not limited to (cardiopulmonary) bypass surgery, vascular surgery,and vascular grafts.

In a seventy-fifth aspect, any one or more compound(s) of Formula I canbe used in the preparation of a medicament for the treatment of adisease or condition related to Flt-3 selected from the group consistingof malignancies, including, but not limited to, glioma, glioblastoma,brain metastases, lung cancer, breast cancer, colorectal cancer,prostate cancer, gastric cancer, esophageal cancer, pancreatic cancer,ovarian cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiplemyeloma, acute lymphocytic leukemia, acute myeloid leukemia, acutemyeloid leukemia with trilineage myelodysplasia, acute promyelocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia,chronic neutrophilic leukemia, acute undifferentiated leukemia,anaplastic large-cell lymphoma, prolymphocyte leukemia, juvenilemyelomonocyctic leukemia, adult T-cell acute lymphocytic leukemia,T-cell type acute lymphocytic leukemia, B-cell type acute lymphocyticleukemia, mixed lineage leukemia, multiple myeloma, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myeloblastic leukemia,chronic myelomonocytic leukemia; other diseases including psoriasis,atopic dermatitis, axonal degeneration, acute transverse myelitis,amyotrophic lateral sclerosis, infantile spinal muscular atrophy,juvenile spinal muscular atrophy, Creutzfeldt-Jakob disease, subacutesclerosing panencephalitis, organ rejection, bone marrow transplantrejection, non-myeloablative bone marrow transplant rejection,ankylosing spondylitis, aplastic anemia, Behcet's disease,graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia,Wegener's granulomatosis, hyper IgE syndrome, idiopathicthrombocytopenia purpura, Myasthenia gravis, type 1 diabetes mellitus,rheumatoid arthritis, Crohn's disease, multiple sclerosis, systemiclupus erythematosus, myelodysplastic syndrome, thrombocythemia,essential thrombocytosis, angiogenic myeloid metaplasia, myelofibrosis,myelofibrosis with myeloid metaplasia, chronic idiopathic myelofibrosis,polycythemia vera, anemia, leukopenia, neutropenia, thrombocytopenia,granulocytopenia, and pancytopenia.

In a seventy-sixth aspect, any one or more compound(s) of Formula I canbe used in the preparation of a medicament for the treatment of adisease or condition related to Trk selected from the group consistingof malignancies, including, but not limited to, prostate cancer, smallcell lung cancer, non-small cell lung cancer, Wilms tumors, mesoblasticnephroma, infantile fibrosarcoma, neuroblastoma, brain cancer, squamouscell cancer, bladder cancer, gastric cancer, pancreatic cancer, breastcancer, head and neck cancer, esophageal cancer, colorectal cancer,renal cancer, hepatocellular cancer, ovarian cancer, gynecologicalcancer, thyroid cancer, cervical cancer, ewings tumor, tumors of thecentral and peripheral nervous system, melanoma, multiple myeloma, acutemyelogenous leukemia, and myeloid leukemia; neuropathies, including, butnot limited to, stroke, multiple sclerosis, Parkinson's disease,Alzheimer's disease, transverse myelitis, and encephalitis; pain,including, but not limited to, chronic pain, acute pain, inflammatorypain, neuropathic pain, and pain associated with cancer, surgery, orbone fracture; bone-related diseases, including, but not limited to,metastatic bone disease, treatment-induced bone loss, osteoporosis,rheumatoid arthritis, ankylosing spondylitis, Paget's disease, andperiodontal disease; other diseases, including, but not limited to,asthma, arthritis, diabetic retinopathy, macular degeneration,psoriasis, acute and chronic inflammation, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,arterial restenosis, fibrosarcoma, osteosarcoma, panic disorder, andinfectious disease (e.g. Typanosoma cruzi infection (Chagas disease)).

In a seventy-seventh aspect, any one or more compound(s) of Formula Ican be used in the preparation of a medicament for the treatment of adisease or condition selected from the group consisting of rheumatoidarthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis,systemic sclerosis, demyelinating disorders, multiple sclerosis, CharcotMarie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer'sdisease, Parkinson's disease, global ischemia, ulcerative colitis,Crohn's disease, immune thrombocytopenic purpura, atherosclerosis,systemic lupus erythematosis, myelopreparation for autologoustransplantation, transplant rejection, glomerulonephritis, interstitialnephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy,renal hypertrophy, type I diabetes, acute pain, inflammatory pain,neuropathic pain, acute myeloid leukemia, melanoma, multiple myeloma,breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovariancancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bonemetastases, brain metastases, gastrointestinal stromal tumors, and giantcell tumors.

In a seventy-eighth aspect, any one or more compound(s) of Formula I canbe used in the preparation of a medicament for the treatment of adisease or condition selected from the group consisting of rheumatoidarthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis,multiple sclerosis, Alzheimer's disease, Parkinson's disease, globalischemia, renal hypertrophy, acute myeloid leukemia, melanoma, multiplemyeloma, breast cancer, prostate cancer, pancreatic cancer,glioblastoma, neurofibromatosis, brain metastases, and gastrointestinalstromal tumors.

In a seventy-ninth aspect, one or more compounds as described hereinthat are Kit inhibitors can be used in the preparation of a medicamentfor the treatment of rheumatoid arthritis, gastrointestinal stromaltumors, melanoma or neurofibromatosis.

In an eightieth aspect, one or more compounds as described herein thatare Fms selective inhibitors can be used in the preparation of amedicament for the treatment of multiple sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, rheumatoid arthritis,osteoarthritis, osteoporosis, peri-prosthetic osteolysis,glomerulonephritis, interstitial nephritis, Lupus nephritis, diabeticnephropathy, or renal hypertrophy.

In an eighty-first aspect, one or more compounds as described hereinthat are Fms selective inhibitors that effectively cross the blood brainbarrier can be used in the preparation of a medicament for the treatmentof multiple sclerosis, glioblastoma, Alzheimer's disease, Parkinson'sdisease, or global ischemia.

In an eighty-second aspect, one or more compounds as described hereinthat are Fms selective inhibitors that do not effectively cross theblood brain barrier can be used in the preparation of a medicament forthe treatment of rheumatoid arthritis, osteoarthritis, osteoporosis,peri-prosthetic osteolysis, glomerulonephritis, interstitial nephritis,Lupus nephritis, diabetic nephropathy, or renal hypertrophy.

In an eighty-third aspect, one or more compounds as described hereinthat are dual Fms/Kit inhibitors can be used in the preparation of amedicament for the treatment of breast cancer, prostate cancer, multiplemyeloma, melanoma, acute myeloid leukemia, glioblastoma, brainmetastases, neurofibromatosis, gastrointestinal stromal tumors,rheumatoid arthritis, or multiple sclerosis.

In an eighty-fourth aspect, one or more compounds as described hereinthat are dual Fms/Flt-3 inhibitors can be used in the preparation of amedicament for the treatment of breast cancer, prostate cancer, multiplemyeloma, melanoma, acute myeloid leukemia, glioblastoma, brainmetastases, neurofibromatosis, gastrointestinal stromal tumors,rheumatoid arthritis, or multiple sclerosis, preferably wherein thedisease is acute myeloid leukemia.

In an eighty-fifth aspect, one or more compounds as described hereinthat are dual Fms/Trk inhibitors can be used in the preparation of amedicament for the treatment of pancreatic cancer, prostate cancer, andmultiple myeloma.

In an eighty-sixth aspect, there are provided compounds of Formula I forthe treatment of a disease or condition related to Kit selected from thegroup consisting of malignancies, including, but not limited to, mastcell tumors, small cell lung cancer, non-small cell lung cancer (NSCLC),testicular cancer, pancreatic cancer, breast cancer, prostate cancer,merkel cell carcinoma, carcinomas of the female genital tract, sarcomasof neuroectodermal origin, colorectal carcinoma, carcinoma in situ,gastrointestinal stromal tumors (GISTs), multiple myeloma, tumorangiogenesis, brain metastases, glioblastoma, astrocytoma,neuroblastoma, neurofibromatosis (including Schwann cell neoplasiaassociated with neurofibromatosis), acute myeloid leukemia, acutelymphocytic leukemia, chronic myeloid leukemia, mastocytosis, melanoma,and canine mast cell tumors; cardiovascular disease, including but notlimited to atherosclerosis, cardiomyopathy, heart failure, pulmonaryarterial hypertension and pulmonary fibrosis; inflammatory andautoimmune indications, including, but not limited to, allergy,anaphylaxis, asthma, rheumatoid arthritis, allergic rhinitis, multiplesclerosis, inflammatory bowel disease, transplant rejection,hypereosinophilia, urticaria and dermatitis; gastrointestinalindications, including but not limited to gastroesophageal refluxdisease (GERD), esophagitis, and gastrointestinal tract ulcers;ophthalmic indications, including but not limited to uveitis andretinitis; and neurologic indications, including but not limited tomigraine.

In an eighty-seventh aspect there are provided compounds of Formula Ifor the treatment of a disease or condition related to Fms selected fromthe group consisting of inflammatory and autoimmune indications,including, but not limited to, rheumatoid arthritis, osteoarthritis,psoriatic arthritis, psoriasis, dermatitis, ankylosing spondylitis,polymyositis, dermatomyositis, systemic sclerosis, juvenile idiopathicarthritis, polymyalgia rheumatica, Sjogren's disease, Langerhan's cellhistiocytosis (LCH), Still's disease, inflammatory bowel disease,ulcerative colitis, Crohn's disease, systemic lupus erythematosis (SLE),immune thrombocytopenic purpura (ITP), myelopreparation for autologoustransplantation, transplant rejection, chronic obstructive pulmonarydisease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome(macrophage activation syndrome), multicentric reticulohistiocytosis,and atherosclerosis; metabolic disorders, including, but not limited to,Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia,obesity, and lipolysis; disorders of bone structure, mineralization andbone formation and resorption, including, but not limited to,osteoporosis, osteodystrophy, increased risk of fracture, Paget'sdisease, hypercalcemia, infection-mediated osteolysis (e.g.osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis;kidney and genitourinary diseases, including, but not limited to,endometriosis, nephritis (e.g. glomerulonephritis, interstitialnephritis, Lupus nephritis), tubular necrosis, diabetes-associated renalcomplications (e.g. diabetic nephropathy), and renal hypertrophy;disorders of the nervous system, including, but not limited to,demyelinating disorders (e.g. multiple sclerosis, Charcot Marie Toothsyndrome), amyotrophic lateral sclerosis (ALS), myasthenia gravis,chronic demyelinating polyneuropathy, other demyelinating disorders,stroke, Alzheimer's disease and Parkinson's disease; pain, including,but not limited to, chronic pain, acute pain, inflammatory pain,neuropathic pain, bone pain; malignancies, including, but not limitedto, multiple myeloma, acute myeloid leukemia (AML), chronic myeloidleukemia (CML), lung cancer, pancreatic cancer, prostate cancer, breastcancer, ovarian cancer, neuroblastoma, sarcoma, osteosarcoma, giant celltumors, (e.g. giant cell tumor of bone, giant cell tumor of tendonsheath (TGCT)), pigmented villonodular synovitis (PVNS), tumorangiogenesis, melanoma, glioblastoma multiforme, glioma, other tumors ofthe central nervous system, brain metastases, osteolytic bonemetastases, metastasis of tumors to other tissues, and other chronicmyeloproliferative diseases such as myelofibrosis; vasculitis, includingbut not limited to collagen vascular disease, polyarteritis nodosa,Behcet's disease, sarcoidosis, familiar Mediterranean fever,Churg-Strauss vasculitis, temporal arteritis, giant cell arteritis,Takayasu's arteritis; ophthalmic indications, including but not limitedto uveitis, scleritis, retinitis, age related macular degeneration,choroidal neovascularization, diabetic retinopathy; inherited disorders,including but not limited to cherubism, neurofibromatosis; infectiousdisease indications, including but not limited to infections associatedwith human immunodeficiency virus, hepatitis B virus, hepatitis C virus,human granulocytic anaplasmosis; lysosomal storage disorders, includingbut not limited to Gaucher's disease, Fabry's disease, Niemann-Pickdisease; gastrointestinal indications, including but not limited toliver cirrhosis; pulmonary indications, including but not limited topulmonary fibrosis, acute lung injury (e.g. ventilator-induced, smoke-or toxin-induced); global ischemia, and surgical indications, includingbut not limited to (cardiopulmonary) bypass surgery, vascular surgery,and vascular grafts.

In an eighty-eighth aspect, there are provided compounds of Formula Ifor the treatment of a disease or condition related to Flt-3 selectedfrom the group consisting of malignancies, including, but not limitedto, glioma, glioblastoma, brain metastases, lung cancer, breast cancer,colorectal cancer, prostate cancer, gastric cancer, esophageal cancer,pancreatic cancer, ovarian cancer, non-Hodgkin's lymphoma, Hodgkin'slymphoma, multiple myeloma, acute lymphocytic leukemia, acute myeloidleukemia, acute myeloid leukemia with trilineage myelodysplasia, acutepromyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloidleukemia, chronic neutrophilic leukemia, acute undifferentiatedleukemia, anaplastic large-cell lymphoma, prolymphocyte leukemia,juvenile myelomonocyctic leukemia, adult T-cell acute lymphocyticleukemia, T-cell type acute lymphocytic leukemia, B-cell type acutelymphocytic leukemia, mixed lineage leukemia, multiple myeloma, chronicmyelocytic leukemia, acute lymphoblastic leukemia, acute myeloblasticleukemia, chronic myelomonocytic leukemia; other diseases includingpsoriasis, atopic dermatitis, axonal degeneration, acute transversemyelitis, amyotrophic lateral sclerosis, infantile spinal muscularatrophy, juvenile spinal muscular atrophy, Creutzfeldt-Jakob disease,subacute sclerosing panencephalitis, organ rejection, bone marrowtransplant rejection, non-myeloablative bone marrow transplantrejection, ankylosing spondylitis, aplastic anemia, Behcet's disease,graft-versus-host disease, Graves' disease, autoimmune hemolytic anemia,Wegener's granulomatosis, hyper IgE syndrome, idiopathicthrombocytopenia purpura, Myasthenia gravis, type 1 diabetes mellitus,rheumatoid arthritis, Crohn's disease, multiple sclerosis, systemiclupus erythematosus, myelodysplastic syndrome, thrombocythemia,essential thrombocytosis, angiogenic myeloid metaplasia, myelofibrosis,myelofibrosis with myeloid metaplasia, chronic idiopathic myelofibrosis,polycythemia vera, anemia, leukopenia, neutropenia, thrombocytopenia,granulocytopenia, and pancytopenia.

In an eighty-ninth aspect, there are provided compounds of Formula I forthe treatment of a disease or condition related to Trk selected from thegroup consisting of malignancies, including, but not limited to,prostate cancer, small cell lung cancer, non-small cell lung cancer,Wilms tumors, mesoblastic nephroma, infantile fibrosarcoma,neuroblastoma, brain cancer, squamous cell cancer, bladder cancer,gastric cancer, pancreatic cancer, breast cancer, head and neck cancer,esophageal cancer, colorectal cancer, renal cancer, hepatocellularcancer, ovarian cancer, gynecological cancer, thyroid cancer, cervicalcancer, ewings tumor, tumors of the central and peripheral nervoussystem, melanoma, multiple myeloma, acute myelogenous leukemia, andmyeloid leukemia; neuropathies, including, but not limited to, stroke,multiple sclerosis, Parkinson's disease, Alzheimer's disease, transversemyelitis, and encephalitis; pain, including, but not limited to, chronicpain, acute pain, inflammatory pain, neuropathic pain, and painassociated with cancer, surgery, or bone fracture; bone-relateddiseases, including, but not limited to, metastatic bone disease,treatment-induced bone loss, osteoporosis, rheumatoid arthritis,ankylosing spondylitis, Paget's disease, and periodontal disease; otherdiseases, including, but not limited to, asthma, arthritis, diabeticretinopathy, macular degeneration, psoriasis, acute and chronicinflammation, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, atherosclerosis, arterial restenosis,fibrosarcoma, osteosarcoma, panic disorder, and infectious disease (e.g.Typanosoma cruzi infection (Chagas disease)).

In a ninetieth aspect, there are provided compounds of Formula I for thetreatment of a disease or condition selected from the group consistingof rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prostheticosteolysis, systemic sclerosis, demyelinating disorders, multiplesclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis,Alzheimer's disease, Parkinson's disease, global ischemia, ulcerativecolitis, Crohn's disease, immune thrombocytopenic purpura,atherosclerosis, systemic lupus erythematosis, myelopreparation forautologous transplantation, transplant rejection, glomerulonephritis,interstitial nephritis, Lupus nephritis, tubular necrosis, diabeticnephropathy, renal hypertrophy, type I diabetes, acute pain,inflammatory pain, neuropathic pain, acute myeloid leukemia, melanoma,multiple myeloma, breast cancer, prostate cancer, pancreatic cancer,lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis,osteolytic bone metastases, brain metastases, gastrointestinal stromaltumors, and giant cell tumors.

In a ninety-first aspect, there are provided compounds of Formula I forthe treatment of a disease or condition selected from the groupconsisting of rheumatoid arthritis, osteoarthritis, osteoporosis,peri-prosthetic osteolysis, multiple sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, renal hypertrophy, acute myeloidleukemia, melanoma, multiple myeloma, breast cancer, prostate cancer,pancreatic cancer, glioblastoma, neurofibromatosis, brain metastases,and gastrointestinal stromal tumors.

In a ninety-second aspect, there are provided compounds as describedherein that are Kit inhibitors for the treatment of a disease orcondition selected from the group consisting of rheumatoid arthritis,gastrointestinal stromal tumors, melanoma and neurofibromatosis.

In a ninety-third aspect, there are provided compounds as describedherein that are Fms selective inhibitors for the treatment of a diseaseor condition selected from the group consisting of multiple sclerosis,Alzheimer's disease, Parkinson's disease, global ischemia, rheumatoidarthritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis,glomerulonephritis, interstitial nephritis, Lupus nephritis, diabeticnephropathy, and renal hypertrophy.

In a ninety-fourth aspect, there are provided compounds as describedherein that are Fms selective inhibitors that effectively cross theblood brain barrier for the treatment of a disease or condition selectedfrom the group consisting of multiple sclerosis, glioblastoma,Alzheimer's disease, Parkinson's disease, and global ischemia.

In a ninety-fifth aspect, there are provided compounds as describedherein that are Fms selective inhibitors that do not effectively crossthe blood brain barrier for the treatment of a disease or conditionselected from the group consisting of rheumatoid arthritis,osteoarthritis, osteoporosis, peri-prosthetic osteolysis,glomerulonephritis, interstitial nephritis, Lupus nephritis, diabeticnephropathy, and renal hypertrophy.

In a ninety-sixth aspect, there are provided compounds as describedherein that are dual Fms/Kit inhibitors for the treatment of a diseaseor condition selected from the group consisting of breast cancer,prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia,glioblastoma, brain metastases, neurofibromatosis, gastrointestinalstromal tumors, rheumatoid arthritis, and multiple sclerosis.

In a ninety-seventh aspect, there are provided compounds as describedherein that are dual Fms/Flt-3 inhibitors for the treatment of a diseaseor condition selected from the group consisting of breast cancer,prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia,glioblastoma, brain metastases, neurofibromatosis, gastrointestinalstromal tumors, rheumatoid arthritis, and multiple sclerosis, preferablywherein the disease is acute myeloid leukemia.

In a ninety-eighth aspect, there are provided compounds as describedherein that are dual Fms/Trk inhibitors for the treatment of a diseaseor condition selected from the group consisting of pancreatic cancer,prostate cancer, and multiple myeloma.

In a ninety-ninth aspect, the invention provide a compound of FormulaII:

wherein P¹ and P² are each independently H or an amino protecting group.P³ is H or a hydroxyl protecting group or a labile group. In oneembodiment, P¹ and P² are each independently amino protecting group. Inone embodiment, P³ is H. All the other variables X₁, R², R³, Y₁ and Cy₁are as defined in any of the embodiments of Formula I described herein.

In a 100^(th) aspect, the invention provides a compound of Formula IIa:

wherein P¹ and P² are each independently H or an amino protecting group.P³ is H or a hydroxyl protecting group or a labile group. Z¹ is Br, Clor R², wherein R² is as defined in any of the embodiments of formula Idescried herein. In one embodiment, Z¹ is Cl or Br. In one embodiment,P¹ and P² are each independently amino protecting group. In oneembodiment, P³ is H. All the other variables X₁, R³, Y₁ and Cy₁ are asdefined in any of the embodiments of Formula I described herein.

In a 101^(st) aspect, the invention provides a method of preparing acompound of Formula I. The method includes contacting a compound ofFormula II with an agent under conditions sufficient to form a compoundof Formula I. The agent can be an oxidizing or a reducing agent.Examples of the oxidizing agent include, but are not limited to,Dess-Martin periodinane (DMP). Examples of the reducing agents include,but are not limited to, trialkylsilane. In some embodiments, the methodis provided to prepare any of the compounds set forth in Tables 1 or 2,or any of compounds of Formula I or any compounds as described herein.

In a 102^(nd) aspect, the invention provides a method of preparing acompound of Formulas II or IIa. The method includes contacting acompound of Formula III:

with a compound of Formula IV:

under conditions sufficient to form a compound of Formula II or IIa,wherein Z² is Br, Cl or R² as defined in any of the embodimentsdescribed herein; Z³ is iodo, a leaving group or a labile group; P¹ andP² are each independently an amino protecting group. In one embodiment,Z² is Cl or Br and Z³ is I. In another embodiment, Z² is R². In someembodiments, Z³ is iodo, methanesulfonyloxy, p-toluenesulfonyloxy,trifluoromethanesulfonyloxy. All the other variables X₁, R³, Y₁ and Cy₁are as defined in any of the embodiments of Formula I described herein.In some embodiments, the method is provided to prepare any of thecompounds set forth in Tables 1 or 2, or any of compounds of Formula Ior any of the compounds as described herein. In some embodiments, acompound of Formula IV is an aldehyde selected from those set forth inTables 3, 4, 5 and/or 6. In some embodiments, compounds of Formula IIIis a pyrrolo[2,3-b]pyridine compound selected from those set forth inTables 4, 5 and/or 6. In some embodiments, compounds of formula IV is apyrrolo[2,3-b]pyrimidine selected from those set forth in Table 5.

Any one or more of compounds of Formula I demonstrate desirableinhibitory activity on one or more of Fms, Kit, Flt3 and Trk kinases,including desirable activity profiles as described herein withselectivity relative to other kinases. Compounds of Formula I furtherdemonstrate one or more desirable properties, including enhancedpharmacokinetic properties, favorable solubility, favorable lack of Cypinhibition, and the like.

Additional aspects and embodiments will be apparent from the followingDetailed Description of the Invention and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following definitions apply unless clearly indicatedotherwise:

It is noted here that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise.

All atoms designated within a Formula described herein, either within astructure provided, or within the definitions of variables related tothe structure, is intended to include any isotope thereof, unlessclearly indicated to the contrary. It is understood that for any givenatom, the isotopes may be present essentially in ratios according totheir natural occurrence, or one or more particular atoms may beenhanced with respect to one or more isotopes using synthetic methodsknown to one skilled in the art. Thus, hydrogen includes for example ¹H,²H, ³H; carbon includes for example ¹¹C, ¹²C, ¹³C, ¹⁴C; oxygen includesfor example ¹⁶O, ¹⁷O, ¹⁸O; nitrogen includes for example ¹³N, ¹⁴N, ¹⁵N;sulfur includes for example ³²S, ³³S, ³⁴S, ³⁵S, ³⁶S, ³⁷S, ³⁸S; fluoroincludes for example ¹⁷F, ¹⁸F, ¹⁹F; chloro includes for example ³⁵Cl,³⁶Cl, ³⁷Cl, ³⁸Cl, ³⁹Cl; and the like.

“Halogen” refer to all halogens, that is, chloro (Cl), fluoro (F), bromo(Br), or iodo (I).

“Haloalkyl,” is meant to include alkyl substituted by one to sevenhalogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₆ haloalkyl” is meant to include trifluoromethyl,difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

“Hydroxyl” or “hydroxy” refer to the group —OH.

“Thiol” refers to the group —SH.

“Lower alkyl” alone or in combination means an alkane-derived radicalcontaining from 1 to 6 carbon atoms (unless otherwise specified) thatincludes a straight chain alkyl or branched alkyl. The straight chain orbranched lower alkyl group is chemically feasible and attached at anyavailable point to provide a stable compound. In many embodiments, alower alkyl is a straight or branched alkyl group containing from 1-6,1-4, 1-3, or 1-2, carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, t-butyl, and the like. In some instances, the optionof the number of carbon atoms in a lower alkyl is specified, forexample, C₁₋₃ alkyl refers to lower alkyl having 1, 2 or 3 carbon atoms.A “substituted lower alkyl” denotes lower alkyl that is independentlysubstituted, unless indicated otherwise, with one or more, preferably 1,2, 3, 4, 5 or 6, also 1, 2, or 3 substituents, as described herein,attached at any available atom to provide a stable compound. For example“fluoro substituted lower alkyl” denotes a lower alkyl group substitutedwith one or more fluoro atoms, such as perfluoroalkyl, where preferablythe lower alkyl is substituted with 1, 2, 3, 4, 5 or 6 fluoro atoms,also 1, 2, or 3 fluoro atoms. It is understood that substitutions arechemically feasible and attached at any available atom to provide astable compound.

“Lower alkoxy” denotes the group —OR^(a), where R^(a) is lower alkyl. Insome instances, the option of the number of carbon atoms in the loweralkyl is specified, for example, C₁₋₃ alkoxy refers to lower alkoxyhaving 1, 2 or 3 carbon atoms. “Substituted lower alkoxy” denotes loweralkoxy in which R^(z) is lower alkyl substituted with one or moresubstituents as indicated herein, for example, in the description ofcompounds of Formula I, including descriptions of substitutedcycloalkyl, phenyl and heteroaryl, attached at any available atom toprovide a stable compound. Preferably, substitution of lower alkoxy iswith 1, 2, 3, 4, 5 or 6 substituents, also 1, 2, or 3 substituents. Forexample “fluoro substituted lower alkoxy” denotes lower alkoxy in whichthe lower alkyl is substituted with one or more fluoro atoms, wherepreferably the lower alkoxy is substituted with 1, 2, 3, 4, 5 or 6fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood thatsubstitutions on alkoxy are chemically feasible and attached at anyavailable atom to provide a stable compound.

“Lower alkylthio” denotes the group —SR^(b), where R^(b) is lower alkyl.In some instances, the option of the number of carbon atoms in the loweralkyl is specified, for example, C₁₋₃ alkylthio refers to loweralkylthio having 1, 2 or 3 carbon atoms. “Substituted lower alkylthio”denotes lower alkylthio in which R^(z) is lower alkyl substituted withone or more substituents as indicated herein, for example, in thedescription of compounds of Formula I, including descriptions ofsubstituted cycloalkyl, phenyl and heteroaryl, attached at any availableatom to provide a stable compound. Preferably, substitution of loweralkylthio is with 1, 2, 3, 4, 5 or 6 substituents, also 1, 2, or 3substituents. For example “fluoro substituted lower alkylthio” denoteslower alkylthio in which the lower alkyl is substituted with one or morefluoro atoms, where preferably the lower alkylthio is substituted with1, 2, 3, 4, 5 or 6 fluoro atoms, also 1, 2, or 3 fluoro atoms. It isunderstood that substitutions on alkylthio are chemically feasible andattached at any available atom to provide a stable compound.

“Lower alkylsulfonyl” denotes the group —S(O)₂R^(c), where R^(c) islower alkyl. In some instances, the option of the number of carbon atomsin the lower alkyl is specified, for example, C₁₋₃ alkylsulfonyl refersto lower alkylsulfonyl having 1, 2 or 3 carbon atoms. “Substituted loweralkylsulfonyl” denotes lower alkysulfonyl in which R^(z) is lower alkylsubstituted with one or more substituents as indicated herein, forexample, in the description of compounds of Formula I, includingdescriptions of substituted cycloalkyl, phenyl and heteroaryl, attachedat any available atom to provide a stable compound. Preferably,substitution of lower alkylsulfonyl is with 1, 2, 3, 4, 5 or 6substituents, also 1, 2, or 3 substituents. For example “fluorosubstituted lower alkylsulfonyl” denotes lower alkylsulfonyl in whichthe lower alkyl is substituted with one or more fluoro atoms, wherepreferably the lower alkylsulfonyl is substituted with 1, 2, 3, 4, 5 or6 fluoro atoms, also 1, 2, or 3 fluoro atoms. It is understood thatsubstitutions on alkylsulfonyl are chemically feasible and attached atany available atom to provide a stable compound.

“Cycloalkyl” refers to saturated or unsaturated, non-aromatic monocycliccarbon ring systems of 3-8, more preferably 3-6, ring members per ring,such as cyclopropyl, cyclopentyl, cyclohexyl, and the like. In someinstances, the option of the number of carbon atoms in the cycloalkyl isspecified, for example, C₁₋₃ cycloalkyl refers to cycloalkyl having 1, 2or 3 carbon atoms. A “substituted cycloalkyl” is a cycloalkyl that isindependently substituted, unless indicated otherwise, with one or more,preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, as describedherein, attached at any available atom to provide a stable compound. Itis understood that substitutions are chemically feasible and attached atany available atom to provide a stable compound.

“Cycloalkylalkyl” refers to an -(alkylene)-cycloalkyl group wherealkylene as defined herein has the indicated number of carbon atoms orif unspecified having six or fewer, preferably four or fewer main chaincarbon atoms; and cycloalkyl is as defined herein has the indicatednumber of carbon atoms. C₃₋₈cycloalkylalkyl is meant to have 3 to 8 ringcarbon atoms. Exemplary cycloalkylalkyl include, e.g.,cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and thelike.

The term “alkylene” by itself or as part of another substituent means alinear or branched saturated divalent hydrocarbon moiety derived from analkane having the number of carbon atoms indicated in the prefix. Forexample, (i.e., C₁₋₆ means one to six carbons; C₁₋₆ alkylene is meant toinclude methylene, ethylene, propylene, 2-methylpropylene, pentylene,hexylene and the like). C₁₋₄ alkylene includes methylene —CH₂—, ethylene—CH₂CH₂—, propylene —CH₂CH₂CH₂—, and isopropylene —CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —CH₂—(CH₂)₂CH₂—, —CH₂—CH(CH₃)CH₂—, —CH₂—C(CH₃)₂—,—CH₂—CH₂CH(CH₃)—. Typically, an alkyl (or alkylene) group will have from1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer,or 6 or fewer carbon atoms being preferred in the present invention.When a prefix is not included to indicate the number of carbon atoms inan alkylene portion, the alkylene moiety or portion thereof will have 12or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms,6 or fewer main chain carbon atoms or 4 or fewer main chain carbonatoms.

“Aryl” by itself or as part of another substituent refers to amonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonmoiety containing 6 to 14 ring carbon atoms. Non-limiting examples ofunsubstituted aryl groups include phenyl, 1-naphthyl, 2-naphthyl and4-biphenyl. Exemplary aryl group, such as phenyl or naphthyl, which maybe optionally fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members.

“Arylalkyl” refers to -(alkylene)-aryl, where the alkylene group is asdefined herein and has the indicated number of carbon atoms, or ifunspecified having six or fewer main chain carbon atoms or four or fewermain chain carbon atoms; and aryl is as defined herein. Examples ofarylalkyl include benzyl, phenethyl, and the like.

A “substituted phenyl” is a phenyl ring that is independentlysubstituted, unless indicated otherwise, with one or more, preferably 1,2, 3, 4 or 5, also 1, 2, or 3 substituents, as described herein,attached at any available atom to provide a stable compound. It isunderstood that substitutions are chemically feasible and attached atany available atom to provide a stable compound.

“Heteroaryl” by itself or as part of another substituent refers to amonocyclic aromatic ring structure containing 5 or 6 ring atoms, or abicyclic aromatic group having 8 to 10 atoms, containing one or more,preferably 1-4, more preferably 1-3, even more preferably 1-2,heteroatoms independently selected from the group consisting of O, S,and N. “5 or 6 membered heteroaryl” alone or in combination refers to amonocyclic aromatic ring structure containing 5 or 6 ring atoms,containing one or more, preferably 1-4, more preferably 1-3, even morepreferably 1-2, heteroatoms independently selected from the groupconsisting of O, S, and N. Heteroaryl is also intended to includeoxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiaryring nitrogen. A carbon or nitrogen atom is the point of attachment ofthe heteroaryl ring structure such that a stable compound is provided.Examples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl,quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl,pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl,isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl,indolyl, triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl,benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl,indazolyl, pteridinyl and thiadiazolyl, and the like. A “substitutedheteroaryl” is a heteroaryl that is independently substituted, unlessindicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also1, 2, or 3 substituents, as described herein, attached at any availableatom to provide a stable compound. It is understood that substitutionsare chemically feasible and attached at any available atom to provide astable compound.

“Heteroarylalkyl” refers to -(alkylene)-heteroaryl, where the alkylenegroup is as defined herein and has the indicated number of carbon atoms,or if unspecified having six or fewer main chain carbon atoms or four orfewer main chain carbon atoms; and heteroaryl is as defined herein.Examples of heteroarylalkyl include 2-pyridylmethyl, 2-thiazolylethyl,and the like.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromaticcycloalkyl group that contains from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized, theremaining ring atoms being C, where one or two C atoms may optionally bereplaced by a carbonyl. The heterocycloalkyl may be a monocyclic, abicyclic or a polycyclic ring system of 3 to 12, preferably 4 to 10 ringatoms, more preferably 5 to 8 ring atoms in which one to five ring atomsare heteroatoms selected from —N═, —N—, —O—, —S—, —S(O)—, or —S(O)₂— andfurther wherein one or two ring atoms are optionally replaced by a—C(O)— group. The heterocycloalkyl can also be a heterocyclic alkyl ringfused with a cycloalkyl, an aryl or a heteroaryl ring. Non limitingexamples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl,imidazolidinyl, pyrazolidinyl, butyrolactam moiety, valerolactam moiety,imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide moiety,piperidine, 1,4-dioxane moiety, morpholinyl, thiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl,pyranyl, pyridine moiety, 3-pyrrolinyl, thiopyranyl, pyrone moiety,tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

“Heterocycloalkylalkyl” refers to -(alkylene)-heterocycloalkyl, wherethe alkylene group is as defined herein and has the indicated number ofcarbon atoms, or if unspecified having six or fewer main chain carbonatoms or four or fewer main chain carbon atoms; and heterocycloalkyl isas defined herein. Examples of heterocycloalkylalkyl include2-pyridylmethyl, 2-thiazolylethyl, and the like.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in T. W. Greene and P. G.Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006),Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison andHarrison et al., COMPENDIUM OF SYNTHETIC ORGANIC METHODS, Vols. 1-8(John Wiley and Sons. 1971-1996). Representative amino protecting groupsinclude formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl(CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethyl silylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACIDCHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).Representative hydroxyl protecting groups include, but are not limitedto, acetyl, benzoyl, dimethoxytrityl, methoxyethyoxymethyl,methoxymethyl, p-methoxybenzyl, tetrahydropyranyl, methylthiomethyl,trityl, t-butyldimethylsilyloxymethyl and trialkylsilyl, such as TMS,TIPS and the like.

As used herein, “Leaving group” or “Labile group” has the meaningconventionally associated with it in synthetic organic chemistry, i.e.,an atom or a group capable of being displaced by a nucleophile andincludes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy,arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy,mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g.,2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.

“Tautomer” means compounds produced by the phenomenon wherein a protonof one atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The tautomers also referto one of two or more structural isomers that exist in equilibrium andare readily converted from one isomeric form to another. Examples ofinclude keto-enol tautomers, such as acetone/propen-2-ol, imine-enaminetautomers and the like, ring-chain tautomers, such asglucose/2,3,4,5,6-pentahydroxy-hexanal and the like, the tautomericforms of heteroaryl groups containing a —N═C(H)—NH— ring atomarrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles,and tetrazoles. Where the compound contains, for example, a keto oroxime group or an aromatic moiety, tautomeric isomerism (tautomerism′)can occur. The compounds described herein may have one or more tautomersand therefore include various isomers. A person of ordinary skill in theart would recognize that other tautomeric ring atom arrangements arepossible. All such isomeric forms of these compounds are expresslyincluded in the present invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. “Hydrate” refers toa complex formed by combination of water molecules with molecules orions of the solute. “Solvate” refers to a complex formed by combinationof solvent molecules with molecules or ions of the solute. The solventcan be an organic compound, an inorganic compound, or a mixture of both.Solvate is meant to include hydrate. Some examples of solvents include,but are not limited to, methanol, N,N-dimethylformamide,tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds of the presentinvention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe present invention and are intended to be within the scope of thepresent invention

As used herein, the term “Fms and Kit related disease or condition”refers to a disease or condition in which the biological function of aFms protein kinase, including any mutation thereof, a Kit proteinkinase, including any mutation thereof, or both a Fms and Kit proteinkinase, including any mutations thereof, affects the development,course, and/or symptoms of the disease or condition, and/or in whichmodulation of the Fms and/or Kit protein kinase alters the development,course, and/or symptoms of the disease or condition. A Fms and/or Kitrelated disease or condition includes a disease or condition for whichmodulation provides a therapeutic benefit, e.g. wherein treatment with aFms and/or Kit protein kinase inhibitor, preferably a dual Fms/Kitinhibitor, including one or more compound(s) described herein, providesa therapeutic benefit to the subject suffering from or at risk of thedisease or condition.

As used herein, the term “Fms related disease or condition” and the likerefers to a disease or condition in which the biological function of aFms protein kinase, including any mutations thereof, affects thedevelopment, course, and/or symptoms of the disease or condition, and/orin which modulation of the Fms protein kinase alters the development,course, and/or symptoms of the disease or condition. The Fms relateddisease or condition includes a disease or condition for which Fmsinhibition provides a therapeutic benefit, e.g. wherein treatment with aFms inhibitor, preferably a Fms selective inhibitor including one ormore compound(s) described herein, provides a therapeutic benefit to thesubject suffering from or at risk of the disease or condition.

As used herein, the terms “Kit related disease or condition” and thelike refers to a disease or condition in which the biological functionof a Kit protein kinase, including any mutations thereof, affects thedevelopment, course, and/or symptoms of the disease or condition, and/orin which modulation of the Kit protein kinase alters the development,course, and/or symptoms of the disease or condition. The Kit relateddisease or condition includes a disease or condition for which Kitinhibition provides a therapeutic benefit, e.g. wherein treatment with aKit inhibitor, including one or more compound(s) described herein,provides a therapeutic benefit to the subject suffering from or at riskof the disease or condition.

As used herein, the term “dual Fms/Kit inhibitor” refers to a compoundthat inhibits both Fms and Kit protein kinases, i.e. a compound havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a generally accepted Fms kinase activity assay and havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a comparable generally accepted Kit kinase activity assay,wherein the activity is approximately equipotent on each. Compounds areconsidered approximately equipotent if the ratio of IC₅₀ for Kit kinaseactivity divided by the IC₅₀ for Fms kinase activity is in the range of20 to 0.05, also 10 to 0.1, also 5 to 0.2. Such compounds are effectivein treating a disease or condition that is either or both of a Fmsrelated and Kit related disease or condition. Such compounds arepreferably, but not necessarily, selective with respect to other proteinkinases, i.e. when compared to another protein kinase, the IC₅₀ for theother kinase divided by the IC₅₀ for Fms kinase (and/or Kit kinase)is >20, also >30, also >40, also >50, also >60, also >70, also >80,also >90, also >100. Preferably, the compounds are selective relative toother protein kinases including, but not limited to, CSK, Insulinreceptor kinase, AMPK, PDGFR or VEGFR. While it is understood that adual Fms/Kit inhibitor may be used to treat any Fms related disease orcondition, the dual inhibition of Fms and Kit provides beneficialeffects in treating certain diseases or conditions, including, but notlimited to, breast cancer, prostate cancer, multiple myeloma, melanoma,acute myeloid leukemia, glioblastoma, brain metastases,neurofibromatosis, gastrointestinal stromal tumors, rheumatoidarthritis, or multiple sclerosis.

As used herein, the term “dual Fms/Flt-3 inhibitor” refers to a compoundthat inhibits both Fms and Flt-3 protein kinases, i.e. a compound havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a generally accepted Fms kinase activity assay and havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a comparable generally accepted Flt-3 kinase activityassay, wherein the activity is approximately equipotent on each.Compounds are considered approximately equipotent if the ratio of IC₅₀for Flt-3 kinase activity divided by the IC₅₀ for Fms kinase activity isin the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. Suchcompounds are effective in treating a disease or condition that iseither or both of a Fms related and Flt-3 related disease or condition.Such compounds are preferably, but not necessarily, selective withrespect to other protein kinases, i.e. when compared to another proteinkinase, the IC₅₀ for the other kinase divided by the IC₅₀ for Fms kinase(and/or Flt3 kinase) is >20, also >30, also >40, also >50, also >60,also >70, also >80, also >90, also >100. Preferably, the compounds areselective relative to other protein kinases including, but not limitedto, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. While it isunderstood that a dual Fms/Flt-3 inhibitor may be used to treat any Fmsrelated mediated disease or condition, the dual inhibition of Fms andFlt-3 provides beneficial effects in treating certain diseases orconditions, including, but not limited to, breast cancer, prostatecancer, multiple myeloma, melanoma, acute myeloid leukemia,glioblastoma, brain metastases, neurofibromatosis, gastrointestinalstromal tumors, rheumatoid arthritis, or multiple sclerosis.

As used herein, the term “dual Fms/Trk inhibitor” refers to a compoundthat inhibits both Fms and Trk protein kinases, i.e. a compound havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a generally accepted Fms kinase activity assay and havingan IC₅₀ of less than 500 nm, less than 100 nM, less than 50 nM, lessthan 20 nM, less than 10 nM, less than 5 nM, or less than 1 nM asdetermined in a comparable generally accepted Trk kinase activity assay(i.e. any one or more of TrkA, TrkB and TrkC), wherein the activity isapproximately equipotent on each. Compounds are considered approximatelyequipotent if the ratio of IC₅₀ for Trk kinase activity (i.e. at leastone of TrkA, TrkB and TrkC) divided by the IC₅₀ for Fms kinase activityis in the range of 20 to 0.05, also 10 to 0.1, also 5 to 0.2. Suchcompounds are effective in treating a disease or condition that iseither or both of a Fms related and Trk related disease or condition.Such compounds are preferably, but not necessarily, selective withrespect to other protein kinases, i.e. when compared to another proteinkinase, the IC₅₀ for the other kinase divided by the IC₅₀ for Fms kinase(and/or Trk kinase) is >20, also >30, also >40, also >50, also >60,also >70, also >80, also >90, also >100. Preferably, the compounds areselective relative to other protein kinases including, but not limitedto, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR. While it isunderstood that a dual Fms/Trk inhibitor may be used to treat any Fmsrelated mediated disease or condition, the dual inhibition of Fms andTrk provides beneficial effects in treating certain diseases orconditions, including, but not limited to, pancreatic cancer, prostatecancer, and multiple myeloma.

As used herein, the term “Fms selective inhibitor” refers to a compoundthat selectively inhibits Fms kinase relative to Kit kinase, i.e. acompound having an IC₅₀ of less than 500 nm, less than 100 nM, less than50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than 1nM as determined in a generally accepted Fms kinase activity assay andwhen determined in a comparable generally accepted Kit kinase activityassay will have a ratio of IC₅₀ for Kit kinase divided by the IC₅₀ forFms kinase of >20, also >30, also >40, also >50, also >60, also >70,also >80, also >90, also >100. Such compounds are effective in treatinga disease or condition that is Fms protein kinase mediated, withouteffecting Kit protein kinase. Such compounds are preferably, but notnecessarily, selective with respect to other protein kinases, i.e. whencompared to another protein kinase, the IC₅₀ for the other kinasedivided by the IC₅₀ for Fms kinase is >20, also >30, also >40, also >50,also >60, also >70, also >80, also >90, also >100. Preferably, thecompounds are selective relative to other protein kinases including, butnot limited to, CSK, Insulin receptor kinase, AMPK, PDGFR or VEGFR.While it is understood that a Fms selective inhibitor may be used totreat any Fms related disease or condition, the Fms selectivity providesbeneficial effects in treating certain diseases or conditions,including, but not limited to, multiple sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, rheumatoid arthritis,osteoarthritis, osteoporosis, peri-prosthetic osteolysis,glomerulonephritis, interstitial nephritis, Lupus nephritis, diabeticnephropathy, or renal hypertrophy.

As used herein, the term “blood brain barrier” refers to the physicalbarrier in the circulation system that prevents many substances,including certain small molecule drugs, from entering into the centralnervous system (CNS). Drugs which are intended to interact withmolecular targets in the CNS must cross the blood brain barrier to reachtheir intended targets. Conversely, peripherally acting agents shouldnot cross the blood brain barrier so as to avoid any CNS related sideeffects. The ability of a compound to penetrate the blood brain barrieris expressed as the blood brain barrier permeability or the ratio of thesteady-state concentrations of the compound in the brain and in theblood. The experimental blood brain barrier permeability can be measuredby in vivo methods. Various methods can be employed for measuring thefraction of compound transported from the blood to brain tissue,including brain blood partitioning, brain perfusion, brain uptake index,and intracerebral microdialysis. However, these in vivo methods arelaborious and low-throughput in nature. In practice, in silicocomputational methods are often used to predict the blood brain barrierpermeability prior to in vivo confirmation. Most of the blood brainbarrier models that have been built so far are based on the assumptionthat the majority of the compounds are transported across the bloodbrain barrier by passive diffusion. Of all the physicochemicalproperties, polar surface area (PSA) shows the best correlation with theblood brain barrier permeability for passively diffused compounds.Empirical evidence suggests that compounds having a polar surface areaof 100 or greater typically have a low probability of crossing the bloodbrain barrier. Polar surface area is readily calculated from thecompound structure using a published algorithm (Ertl et al., J. Med.Chem. 2000, 43:3714-3717). While it is understood that a Fms selectiveinhibitor may be used to treat any Fms related disease or condition,compounds that effectively cross the blood brain barrier providebeneficial effects in treating certain diseases or conditions,including, but not limited to, multiple sclerosis, Alzheimer's disease,Parkinson's disease, and global ischemia, while compounds that do noteffectively cross the blood brain barrier provide beneficial effects intreating certain diseases or conditions, including, but not limited to,rheumatoid arthritis, osteoarthritis, osteoporosis, peri-prostheticosteolysis, glomerulonephritis, interstitial nephritis, Lupus nephritis,diabetic nephropathy, or renal hypertrophy.

As used herein, the terms “treat”, “treating”, “therapy”, “therapies”,and like terms refer to the administration of material, e.g., any one ormore compound(s) as described herein in an amount effective to prevent,alleviate, or ameliorate one or more symptoms of a disease or condition,i.e., indication, and/or to prolong the survival of the subject beingtreated.

As used herein, the term “solid form” refers to a solid preparation(i.e. a preparation that is neither gas nor liquid) of apharmaceutically active compound that is suitable for administration toan intended animal subject for therapeutic purposes. The solid formincludes any complex, such as a salt, co-crystal or an amorphouscomplex, as well as any polymorph of the compound. The solid form may besubstantially crystalline, semi-crystalline or substantially amorphous.The solid form may be administered directly or used in the preparationof a suitable composition having improved pharmaceutical properties. Forexample, the solid form may be used in a formulation comprising at leastone pharmaceutically acceptable carrier or excipient.

As used herein, the term “substantially crystalline” material embracesmaterial which has greater than about 90% crystallinity; and“crystalline” material embraces material which has greater than about98% crystallinity.

As used herein, the term “substantially amorphous” material embracesmaterial which has no more than about 10% crystallinity; and “amorphous”material embraces material which has no more than about 2%crystallinity.

As used herein, the term “semi-crystalline” material embraces materialwhich is greater than 10% crystallinity, but no greater than 90%crystallinity; preferably “semi-crystalline” material embraces materialwhich is greater than 20% crystallinity, but no greater than 80%crystallinity. In one aspect of the present invention, a mixture ofsolid forms of a compound may be prepared, for example, a mixture ofamorphous and crystalline solid forms, e.g. to provide a“semi-crystalline” solid form. Such a “semi-crystalline” solid form maybe prepared by methods known in the art, for example by mixing anamorphous solid form with a crystalline solid form in the desired ratio.In some instances, a compound mixed with acid or base forms an amorphouscomplex; a semi-crystalline solid can be prepared employing an amount ofcompound component in excess of the stoichiometry of the compound andacid or base in the amorphous complex, thereby resulting in an amount ofthe amorphous complex that is based on the stoichiometry thereof, withexcess compound in a crystalline form. The amount of excess compoundused in the preparation of the complex can be adjusted to provide thedesired ratio of amorphous complex to crystalline compound in theresulting mixture of solid forms. For example, where the amorphouscomplex of acid or base and compound has a 1:1 stoichiometry, preparingsaid complex with a 2:1 mole ratio of compound to acid or base willresult in a solid form of 50% amorphous complex and 50% crystallinecompound. Such a mixture of solid forms may be beneficial as a drugproduct, for example, by providing an amorphous component havingimproved biopharmaceutical properties along with the crystallinecomponent. The amorphous component would be more readily bioavailablewhile the crystalline component would have a delayed bioavailability.Such a mixture may provide both rapid and extended exposure to theactive compound.

As used herein, the term “complex” refers to a combination of apharmaceutically active compound and an additional molecular speciesthat forms or produces a new chemical species in a solid form. In someinstances, the complex may be a salt, i.e. where the additionalmolecular species provides an acid/base counter ion to an acid/basegroup of the compound resulting in an acid:base interaction that forms atypical salt. While such salt forms are typically substantiallycrystalline, they can also be partially crystalline, substantiallyamorphous, or amorphous forms. In some instances, the additionalmolecular species, in combination with the pharmaceutically activecompound, forms a non-salt co-crystal, i.e. the compound and molecularspecies do not interact by way of a typical acid:base interaction, butstill form a substantially crystalline structure. Co-crystals may alsobe formed from a salt of the compound and an additional molecularspecies. In some instances, the complex is a substantially amorphouscomplex, which may contain salt-like acid:base interactions that do notform typical salt crystals, but instead form a substantially amorphoussolid, i.e. a solid whose X-ray powder diffraction pattern exhibits nosharp peaks (e.g. exhibits an amorphous halo).

As used herein, the term “stoichiometry” refers to the molar ratio oftwo or more reactants that combine to form a complex, for example, themolar ratio of acid or base to compound that form an amorphous complex.For example, a 1:1 mixture of acid or base with compound (i.e. 1 moleacid or base per mole of compound) resulting in an amorphous solid formhas a 1:1 stoichiometry.

As used herein, the term “composition” refers to a pharmaceuticalpreparation suitable for administration to an intended animal subjectfor therapeutic purposes that contains at least one pharmaceuticallyactive compound, including any solid form thereof. The composition mayinclude at least one pharmaceutically acceptable component to provide animproved formulation of the compound, such as a suitable carrier orexcipient.

The term “pharmaceutically acceptable” indicates that the indicatedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectables.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

“Unit dosage form” refers to a composition intended for a singleadministration to treat a subject suffering from a disease or medicalcondition. Each unit dosage form typically comprises each of the activeingredients of this invention plus pharmaceutically acceptableexcipients. Examples of unit dosage forms are individual tablets,individual capsules, bulk powders, liquid solutions, ointments, creams,eye drops, suppositories, emulsions or suspensions. Treatment of thedisease or condition may require periodic administration of unit dosageforms, for example: one unit dosage form two or more times a day, onewith each meal, one every four hours or other interval, or only one perday. The expression “oral unit dosage form” indicates a unit dosage formdesigned to be taken orally.

In the present context, the terms “synergistically effective” or“synergistic effect” indicate that two or more compounds that aretherapeutically effective, when used in combination, provide improvedtherapeutic effects greater than the additive effect that would beexpected based on the effect of each compound used by itself.

In the context of compounds binding to a target, the terms “greateraffinity” and “selective” indicates that the compound binds more tightlythan a reference compound, or than the same compound in a referencecondition, i.e., with a lower dissociation constant. In someembodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50,100, 200, 400, 500, 1000, or 10,000-fold greater affinity.

As used herein in connection with compounds of the invention, the term“synthesizing” and like terms means chemical synthesis from one or moreprecursor materials.

By “assaying” is meant the creation of experimental conditions and thegathering of data regarding a particular result of the experimentalconditions. For example, enzymes can be assayed based on their abilityto act upon a detectable substrate. A compound or ligand can be assayedbased on its ability to bind to a particular target molecule ormolecules.

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with a particular biomolecule such as a protein kinase. Forexample, an agonist or antagonist of a particular biomolecule modulatesthe activity of that biomolecule, e.g., an enzyme, by either increasing(e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor)the activity of the biomolecule, such as an enzyme. Such activity istypically indicated in terms of an inhibitory concentration (IC₅₀) orexcitation concentration (EC₅₀) of the compound for an inhibitor oractivator, respectively, with respect to, for example, an enzyme.

In the context of the use, testing, or screening of compounds that areor may be modulators, the term “contacting” means that the compound(s)are caused to be in sufficient proximity to a particular molecule,complex, cell, tissue, organism, or other specified material thatpotential binding interactions and/or chemical reaction between thecompound and other specified material can occur.

“Pain” or a “pain condition” can be acute and/or chronic pain,including, without limitation, arachnoiditis; arthritis (e.g.osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout);back pain (e.g. sciatica, ruptured disc, spondylolisthesis,radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g.migraine, cluster headaches, tension headaches); head and facial pain(e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia;hyperpathia; inflammatory pain (e.g. pain associated with irritablebowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn'sdisease, cystitis, pain from bacterial, fungal or viral infection);keloid or scar tissue formation; labor or delivery pain; muscle pain(e.g. as a result of polymyositis, dermatomyositis, inclusion bodymyositis, repetitive stress injury (e.g. writer's cramp, carpal tunnelsyndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g.fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia,entrapment neuropathy, brachial plexus avulsion, occipital neuralgia,gout, reflex sympathetic dystrophy syndrome, phantom limb orpost-amputation pain, postherpetic neuralgia, central pain syndrome, ornerve pain resulting from trauma (e.g. nerve injury), disease (e.g.diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis,neurodegenerative diseases such as Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, or cancer treatment); painassociated with skin disorders (e.g. shingles, herpes simplex, skintumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains,strains, bruises, dislocations, fractures, spinal chord, head); spinalstenosis; surgical pain; tactile allodynia; temporomandibular disorders;vascular disease or injury (e.g. vasculitis, coronary artery disease,reperfusion injury (e.g. following ischemia, stroke, or myocardialinfarcts)); other specific organ or tissue pain (e.g. ocular pain,corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gallbladder, gastrointestinal), joint pain, dental pain, pelvichypersensitivity, pelvic pain, renal colic, urinary incontinence); otherdisease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster,psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease(COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn,gastroesophageal reflux disorder, stomach and duodenal ulcers,functional dyspepsia, bone resorption disease, osteoporosis, cerebralmalaria, bacterial meningitis); or pain due to graft v. host rejectionor allograft rejections.

Kinase Targets and Indications of the Invention

Protein kinases play key roles in propagating biochemical signals indiverse biological pathways. More than 500 kinases have been described,and specific kinases have been implicated in a wide range of diseases orconditions (i.e., indications), including for example withoutlimitation, cancer, cardiovascular disease, inflammatory disease,neurological disease, and other diseases. As such, kinases representimportant control points for small molecule therapeutic intervention.Specific target protein kinases contemplated by the present inventionare described in the art, including, without limitation, protein kinasesas described in U.S. patent application Ser. No. 11/473,347 (see also,PCT publication WO2007002433), the disclosure of which is herebyincorporated by reference with respect to such kinase targets, as wellas the following:

Fms:

Target kinase Fms (i.e., feline McDonough sarcoma) is a member of thefamily of genes originally isolated from the Susan McDonough strain offeline sarcoma viruses. Fms is a transmembrane tyrosine kinase of 108.0kDa coded by chromosome 5q33.2-q33.3 (symbol: CSF1R). The structure ofthe transmembrane receptor Fms comprises two Ig-like domains, aIgC2-like domain, two additional Ig-like domains, a TM domain, and theTK domain.

Fms is the receptor for the macrophage colony-stimulating factor(M-CSF), and is crucial for the growth and differentiation of themonocyte-macrophage lineage. Upon binding of M-CSF to the extracellulardomain of Fms, the receptor dimerizes and trans-autophosphorylatescytoplasmic tyrosine residues.

M-CSF, first described by Robinson and co-workers (Blood. 1969,33:396-9), is a cytokine that controls the production, differentiation,and function of macrophages. M-CSF stimulates differentiation ofprogenitor cells to mature monocytes, and prolongs the survival ofmonocytes. Furthermore, M-CSF enhances cytotoxicity, superoxideproduction, phagocytosis, chemotaxis, and secondary cytokine productionof additional factors in monocytes and macrophages. Examples of suchadditional factors include granulocyte colony stimulating factor(G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSFstimulates hematopoiesis, promotes differentiation and proliferation ofosteoclast progenitor cells, and has profound effects on lipidmetabolism. Furthermore, M-CSF is important in pregnancy.Physiologically, large amounts of M-CSF are produced in the placenta,and M-CSF is believed to play an essential role in trophoblastdifferentiation (Motoyoshi, Int J Hematol. 1998, 67:109-22). Theelevated serum M-CSF levels of early pregnancy may participate in theimmunologic mechanisms responsible for the maintenance of the pregnancy(Flanagan & Lader, Curr Opin Hematol. 1998, 5:181-5).

Aberrant expression and/or activation of Fms has been implicated inacute myeloid leukemia, AML (Ridge et al, Proc. Nat. Acad. Sci., 1990,87:1377-1380). Mutations at codon 301 are believed to lead to neoplastictransformation by ligand independence and constitutive tyrosine kinaseactivity of the receptor. The tyrosine residue at codon 969 has beenshown to be involved in a negative regulatory activity, which isdisrupted by amino acid substitutions. Accordingly, Fms mutations aremost prevalent (20%) in chronic myelomonocytic leukemia and AML type M4(23%), both of which are characterized by monocytic differentiation.

A condition related to AML is chronic myeloid leukemia (CIVIL). Duringthe myeloid blast crisis (BC) of CIVIL, non-random additional chromosomeabnormalities occur in over 80% of patients. However, these cytogeneticchanges have been reported to precede the clinical signs of CML-BC byseveral months to years suggesting that other biological events mayparticipate in the multistep process of acute transformation of CIVIL.The autocrine production of growth factors has been shown to occur inseveral hematological malignancies and particularly in AML. Specchia etal [Br J Haematol. 1992 March; 80(3):310-6] have demonstrated that IL-1beta gene is expressed in almost all cases of CIVIL in myeloid blastcrisis, and that a high proportion of cases showed constitutiveexpression of the M-CSF gene. Many of the same patients in the Specchiaet al study demonstrated simultaneous co-expression of Fms. Afterexposure of leukemic cells to phorbol myristate acetate (PMA), releaseof M-CSF protein was documented in three of five patients studied;however, no significant interleukin-3 (IL-3), granulocyte-macrophagecolony-stimulating factor (GM-CSF) or granulocyte colony-stimulatingfactor (G-CSF), was detected in these patients. This demonstrates thatdifferent patterns of growth factors secretion exist in AML and CML, andthat distinct molecular events are likely involved in the control ofleukemic proliferation.

The observation that production of M-CSF, the major macrophage growthfactor, is increased in tissues during inflammation (Le Meur et al, J.Leukocyte Biology. 2002; 72:530-537) provides a role for Fms in certaindiseases. For example, COPD is characterized by airflow limitation thatis not fully reversible. The airflow limitation is usually progressiveand associated with an abnormal inflammatory response of the lungs tonoxious particles or gases. The chronic inflammation of COPD is observedthrough the airways, parenchyma, and pulmonary vasculature. Theinflammatory cell population consists of neutrophils, macrophages, and Tlymphocytes, along with eosinophils in some patients. Macrophages arepostulated to play an orchestrating role in COPD inflammation byreleasing mediators such as TNF-a, IL-8 and LTB4, which are capable ofdamaging lung structures and/or sustaining neutrophilic inflammation.

Further, M-CSF/fms signaling is critical to osteoclast formation andsurvival of osteoclast precursors. For example, estrogen loss inmenopause results in increased M-CSF and thus increased osteoclastnumber and bone resorption which leads to increased risk of fracture andosteoporosis. Accordingly, blockage of this signal is a target for theinhibition of bone resorption (Teitelbaum, Science. 2000; 289:1504;Rohan, Science. 2000; 289:1508).

Atherosclerosis, an inflammatory disease of the vessel walls, isassociated with significant morbidity and mortality. A beneficial effectfor Fms inhibition in the treatment and prevention of atherosclerosisdepends on several observations (Libby, Nature. 2002; 420:868-874).First, monocytes resident in the arterial intima increase expression ofscavenger receptors and internalize modified lipoproteins. The resultinglipid-laden macrophages develop into foam cells characteristic of theatherosclerotic lesion. Macrophages in atheroma secrete cytokines andgrowth factors involved in lesion progression. Additionally, macrophagesreplicate within the intima. Through Fms, M-CSF activates the transitionfrom monocyte to lipid-laden macrophage and augments expression ofscavenger receptor A. Indeed, atherosclerotic plaques over-express M-CSFwhich is critical for atherosclerotic progression. Mice deficient inM-CSF have been found to experience less severe atherosclerosis thanmice with normal M-CSF (Rajavashisth, et. al., J. Clin. Invest. 1998;101:2702-2710; Qiao, et. al., Am. J. Path. 1997; 150:1687-1699).Accordingly, inhibitors of Fms disrupt M-CSF signaling, compromisingmonocyte to macrophage foam cell progression, macrophage survival andreplication, and cytokine signaling that participates in lesionprogression.

The role of M-CSF and Fms in emphysema appears to involve the regulationof elastin metabolism through control of matrix metalloproteins. M-CSFhas a role in the modulation of the accumulation and function ofalveolar macrophages (AMs) in vivo (Shibata et al, Blood 2001, 98: pp.2845-2852). Osteopetrotic (Op/Op) mice have no detectable M-CSF and showvariable tissue-specific reductions in macrophage numbers. Accordingly,it was hypothesized that AMs would be decreased in number and havealtered function in Op/Op mice because of the absence of M-CSF. Shibataet al found that lung macrophages identified in lung sections weredecreased in number in 20-day-old Op/Op mice but not Op/Op mice olderthan 4 months compared with findings in age-matched littermate controls.The numbers of AMs recovered by bronchioalveolar lavage (BAL) were alsoreduced in young but not adult Op/Op mice compared with controls.Importantly, AMs of Op/Op mice spontaneously release higher levels ofmatrix metalloproteinases (MMPs) than AMs of controls. Consistent withan increased release of MMP, Op/Op mice have abnormal elastin depositionand spontaneously develop emphysema in the absence of molecular orcellular evidence of lung inflammation. Accordingly, the modulation ofmetalloelastase activity in macrophages by M-CSF may control thedegradation of elastin fibers in lungs or blood vessels.

Metastatic cancer cells cause bone destruction, with associatedfracture, pain, deformation, and hypercalcaemia, due to production ofosteoclasticogenic factors including M-CSF by tumor cells (Clohisy etal, Clin. Orthop. 2000, 373: 104-14). Binding of M-CSF to the Fmsproduct stimulates formation of osteoclasts and osteolytic activity(Kodama et al, J. Exp. Med. 1991, 173: 269-72; Feng et al, Endocrinology2002, 143: 4868-74). Accordingly, inhibition of osteoclast activity atthe level of Fms offers a compelling target for amelioration of bonemetastasis.

Nephritis is inflammation of the kidneys. It may be caused for exampleby a bacterial infection of the kidneys or exposure to a toxin. However,nephritis more commonly develops from an abnormal immune reaction, whichcan occur, for example, when an antibody attacks either the kidneyitself or an antigen attached to kidney cells, or when anantigen-antibody complex formed elsewhere in the body attaches to cellsin the kidney. Some types of nephritis involve infiltration of kidneytissues by white blood cells and deposits of antibodies. In other typesof nephritis, inflammation may consist of tissue swelling or scarringwithout white blood cells or antibodies. Furthermore, nephritis canoccur anywhere in the kidneys. With respect to the glomeruli,progressive damage to glomeruli causes urine production to fall andmetabolic waste products to build up in the blood. When damage toglomeruli is severe, inflammatory cells and injured glomerular cellsaccumulate, compressing the capillaries within the glomerulus andinterfering with filtration. Scarring may develop, impairing kidneyfunction and reducing urine production. In some cases, microthrombi mayform in the small blood vessels, further decreasing kidney function.Less commonly, nephritis involves the tubulointerstitial tissues; suchinflammation is called tubulointerstitial nephritis. When inflammationdamages the tubules and the tubulointerstitial tissues, the kidneys maybecome unable to concentrate urine, eliminate (excrete) metabolic wasteproducts from the body, or balance the excretion of sodium and otherelectrolytes, such as potassium. When the tubules and tubulointerstitialtissues are damaged, kidney failure often develops. Accordingly,inhibition of Fms offers a target for therapeutic intervention innephritis due to the modulation of the inflammatory response comprisingthe etiology of the disease.

Lupus nephritis, i.e., renal involvement in systemic lupus erythematosus(SLE), is a common disease manifestation with a poor prognosis. At leastthree potentially overlapping, immuno-pathogenic mechanisms for lupusnephritis are supported by experimental data. First, circulating immunecomplexes consisting chiefly of DNA and anti-DNA are deposited in thekidney. Resulting complement activation and chemotaxis of neutrophilsleads to a local inflammatory process. Second, in situ formation ofantigen and antibody complexes may similarly lead to complementactivation and leucocyte mediated injury. Third, antibodies againstspecific cellular targets may produce renal injury. An additionalmechanism is observed in SLE patients with the antiphospholipid antibodysyndrome. Glomerular thrombosis can result from the hypercoagulabilitythat accompanies antibodies directed against negatively chargedphospholipid-protein complexes (e.g. biologic false positive VDRL,anticardiolipin antibodies, and lupus anticoagulant). Mesangial lupusnephritis is accompanied by normal diagnostic findings or with a milddegree of proteinuria but typically absence of hypertension or abnormalurinary sediment. Focal and diffuse proliferative lupusglomerulonephritis are often associated with the worst prognosis forrenal survival and can be accompanied by nephrotic syndrome, significanthypertension and abnormal urine sediment. Membranous lupus nephritisoften presents with proteinuria, moderate to high grade, but usuallynormal urinary sediment in the absence of hypertension. Mesangial lupusnephropathy is generally associated with an excellent prognosis, whereasproliferative lupus nephropathy, especially diffuse variant, is oftencharacterized by hypertension, red cell casts and significantdeterioration of renal function. Nephrotic syndrome in the absence ofhypertension, active urinary sediment or significant hypocomplementemiasuggest the membranous variant of lupus nephropathy. Membranousnephropathy generally is associated with a good prognosis and relativepreservation of renal function. However, in the presence of persistentnephrotic range proteinuria, membranous lupus nephropathy can, in fact,lead to loss of renal function and end stage renal disease (ESRD).Accordingly, inhibition of Fms offers a target for therapeuticintervention in lupus due to the modulation of the inflammatory responsecomprising the etiology of the disease.

Macrophage accumulation is a prominent feature in many forms ofglomerulonephritis. Local proliferation of macrophages within the kidneyhas been described in human and experimental glomerulonephritis and mayhave an important role in augmenting the inflammatory response. Isbel etal (Nephrol Dial Transplant 2001, 16: 1638-1647) examined therelationship between local macrophage proliferation and renal expressionof M-CSF. Glomerular and tubulointerstitial M-CSF expression was foundto be up-regulated in human glomerulonephritis, being most prominent inproliferative forms of disease. Because this correlates with localmacrophage proliferation, it suggests that increased renal M-CSFproduction plays an important role in regulating local macrophageproliferation in human glomerulonephritis. In a model of renalinflammation (UUO— unilateral ureteric obstruction) anti-Fms antibodytreatment reduced macrophage accumulation (Le Meur et. al., J LeukocyteBiology, 2002, 72: 530-537). Accordingly, inhibition of Fms offers atarget for therapeutic intervention in glomerulonephritis.

Insulin resistance and obesity are hallmarks of type II diabetes and astrong correlation exists between insulin resistance and abdominalvisceral fat accumulation (Bjorntrop, Diabetes Metab. Res. Rev., 1999,15: 427-441). Current evidence indicates that macrophages accumulatingin adipose tissue release TNF-a and other factors that cause adipocytechanges (hypertrophy, lipolysis, reduced insulin sensitivity) and alsopromote insulin resistance in surrounding tissues. Therefore, macrophageaccumulation in type 2 diabetes is important for disease progression.Accordingly, inhibition of Fms has potential in preventing thedevelopment of insulin resistance and hyperglycemia.

Similarly, the observation that production of M-CSF, the majormacrophage growth factor, is increased in tissues during inflammationpoints out a role for Fms in diseases, such as for example inflammatorydiseases. More particularly, because elevated levels of M-CSF are foundin the disease state, modulation of the activity of Fms can amelioratedisease associated with increased levels of M-CSF.

Fms inhibitors may be useful in treating inflammatory and autoimmuneindications, including, but not limited to, rheumatoid arthritis,osteoarthritis, psoriatic arthritis, psoriasis, dermatitis, ankylosingspondylitis, polymyositis, dermatomyositis, systemic sclerosis, juvenileidiopathic arthritis, polymyalgia rheumatica, Sjogren's disease,Langerhan's cell histiocytosis (LCH), Still's disease, inflammatorybowel syndrome, ulcerative colitis, Crohn's disease, systemic lupuserythematosis (SLE), transplant rejection, chronic obstructive pulmonarydisease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome(macrophage activation syndrome), multicentric reticulohistiocytosis,and atherosclerosis; metabolic disorders, including, but not limited to,Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia,obesity, and lipolysis; disorders of bone structure, mineralization andbone formation and resorption, including, but not limited to,osteoporosis, osteodystrophy, increased risk of fracture, Paget'sdisease, hypercalcemia, infection-mediated osteolysis (e.g.osteomyelitis), and peri-prosthetic or wear-debris-mediated osteolysis;kidney and genitourinary diseases, including, but not limited to,endometriosis, nephritis (e.g. glomerulonephritis, interstitialnephritis, Lupus nephritis), tubular necrosis, diabetes-associated renalcomplications (e.g. diabetic nephropathy), and renal hypertrophy;disorders of the central nervous system, including, but not limited to,multiple sclerosis, amyotrophic lateral sclerosis (ALS), myastheniagravis, chronic demyelinating polyneuropathy, other demyelinatingdisorders, stroke, Alzheimer's disease and Parkinson's disease;inflammatory and chronic pain, including, but not limited to, bone pain;malignancies, including, but not limited to, multiple myeloma, acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), lung cancer,pancreatic cancer, prostate cancer, breast cancer, ovarian cancer,neuroblastoma, sarcoma, osteosarcoma, giant cell tumor of bone, giantcell tumor of tendon sheath (TGCT), pigmented villonodular synovitis(PVNS), tumor angiogenesis, melanoma, glioblastoma multiforme, glioma,other tumors of the central nervous system, metastasis of tumors toother tissues, and other chronic myeloproliferative diseases such asmyelofibrosis; vasculitis, including but not limited to collagenvascular disease, polyarteritis nodosa, Behcet's disease, sarcoidosis,familiar Mediterranean fever, Churg-Strauss vasculitis, temporalarteritis, giant cell arteritis, Takayasu's arteritis; ophthalmicindications, including but not limited to uveitis, scleritis, retinitis,age related macular degeneration, choroidal neovascularization, diabeticretinopathy; inherited disorders, including but not limited tocherubism, neurofibromatosis; infectious disease indications, includingbut not limited to infections associated with human immunodeficiencyvirus, hepatitis B virus, hepatitis C virus, human granulocyticanaplasmosis; lysosomal storage disorders, including but not limited toGaucher's disease, Fabry's disease, Niemann-Pick disease;gastrointestinal indications, including but not limited to livercirrhosis; pulmonary indications, including but not limited to pulmonaryfibrosis, acute lung injury (e.g. ventilator-induced, smoke- ortoxin-induced); and surgical indications, including but not limited to(cardiopulmonary) bypass surgery, vascular surgery, and vascular grafts.

Kit:

Target kinase Kit (i.e., feline Hardy-Zuckerman 4 sarcoma viraloncogene) is a 109.9 kDa transmembrane tyrosine kinase encoded bychromosome 4q12 (symbol: KIT). Receptor protein tyrosine kinases (RPTKs)regulate key signal transduction cascades that control cellular growthand proliferation. The Stem Cell Factor (SCF) receptor Kit is a type IIItransmembrane RPTK that includes five extracellular immunoglobulin (IG)domains, a single transmembrane domain, and a split cytoplasmic kinasedomain separated by a kinase insert segment. Kit plays an important rolein the development of melanocytes, mast, germ, and hematopoietic cells.

Stem Cell Factor (SCF) is a protein encoded by the 51 locus, and hasalso been called kit ligand (KL) and mast cell growth factor (MGF),based on the biological properties used to identify it (reviewed inTsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol1997, 153:337-344; Vliagoftis, et al., Clin Immunol 1997, 100:435-440;Broudy, Blood 1997, 90:1345-1364; Pignon, Hermatol Cell Ther 1997,39:114-116; and Lyman, et al., Blood 1998, 91:1101-1134.). Herein theabbreviation SCF refers to the ligand for Kit.

SCF is synthesized as a transmembrane protein with a molecular weight of220 or 248 Dalton, depending on alternative splicing of the mRNA toencode exon 6. The larger protein can be proteolytically cleaved to forma soluble, glycosylated protein which noncovalently dimerizes. Both thesoluble and membrane-bound forms of SCF can bind to and activate Kit.For example, in the skin, SCF is predominantly expressed by fibroblasts,keratinocytes, and endothelial cells, which modulate the activity ofmelanocytes and mast cells expressing Kit. In bone, marrow stromal cellsexpress SCF and regulate hematopoiesis of Kit expressing stem cells. Inthe gastrointestinal tract, intestinal epithelial cells express SCF andaffect the interstitial cells of Cajal and intraepithelial lymphocytes.In the testis, sertoli cells and granulosa cells express SCF whichregulates spermatogenesis by interaction with Kit on germ cells.

According to OMIM, signaling from Kit is essential for primordial germcell growth both in vivo and in vitro. Many downstream effectors of theKIT signaling pathway have been identified in other cell types, but howthese molecules control primordial germ cell survival and proliferationare unknown. Determination of the KIT effectors acting in primordialgerm cells has been hampered by the lack of effective methods tomanipulate easily gene expression in these cells. De Miguel et al.(2002) overcame this problem by testing the efficacy ofretroviral-mediated gene transfer for manipulating gene expression inmammalian germ cells. They found that primordial germ cells cansuccessfully be infected with a variety of types of retroviruses. Theyused this method to demonstrate an important role of the AKT1 inregulating primordial germ cell growth (OMIM MIM Number: 164920: Apr.17, 2006).

Aberrant expression and/or activation of Kit has been implicated in avariety of pathologic states. For example, evidence for a contributionof Kit to neoplastic pathology includes its association with leukemiasand mast cell tumors, small cell lung cancer, testicular cancer, andsome cancers of the gastrointestinal tract and central nervous system.In addition, Kit has been implicated in playing a role in carcinogenesisof the female genital tract sarcomas of neuroectodermal origin, andSchwann cell neoplasia associated with neurofibromatosis. It was foundthat mast cells are involved in modifying the tumor microenvironment andenhancing tumor growth (Yang et al., J Clin Invest. 2003, 112:1851-1861;Viskochil, J Clin Invest. 2003, 112:1791-1793).

Kit inhibitors may be useful in treating malignancies, including, butnot limited to, mast cell tumors, small cell lung cancer, non-small celllung cancer (NSCLC), testicular cancer, pancreatic cancer, breastcancer, merkel cell carcinoma, carcinomas of the female genital tract,sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma insitu, gastrointestinal stromal tumors (GISTs), tumor angiogenesis,glioblastoma, astrocytoma, neuroblastoma, Schwann cell neoplasiaassociated with neurofibromatosis, neurofibromatosis not associated withSchwann cell neoplasia, acute myelocytic leukemia, acute lymphocyticleukemia, chronic myelogenous leukemia, mastocytosis, melanoma, andcanine mast cell tumors; cardiovascular disease, including but notlimited to atherosclerosis, cardiomyopathy, heart failure, pulmonaryhypertension; inflammatory and autoimmune indications, including, butnot limited to, allergy, anaphylaxis, asthma, rheumatoid arthritis,allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome,transplant rejection, hypereosinophilia, urticaria and dermatitis;gastrointestinal indications, including but not limited togastroesophageal reflux disease (GERD), esophagitis, andgastrointestinal tract ulcers; ophthalmic indications, including but notlimited to uveitis and retinitis; and neurologic indications, includingbut not limited to migraine.

Flt3:

Target kinase Flt3 (i.e., Fms-like tyrosine kinase 3) is a transmembranetyrosine kinase of 112.8 kDa encoded by chromosome 13q12 (symbol: FLT3).According to OMIM, Rosnet et al. (Genomics 1991, 9: 380-385) isolated anovel member of the class 3 receptors discussed above. They demonstratedthat this gene of the tyrosine kinase family, called FLT3, has strongsequence similarities with other members of the group.Lymphohematopoietic stem cells serve as a reservoir for virtually allblood cells but make up only approximately 0.01% of human or murinemarrow cells. The ability to isolate and expand this population hasclinical applications in bone marrow transplantations for cancer andgenetic diseases. Small et al. (Proc. Nat. Acad. Sci. 1994, 91: 459-463)cloned the cDNA for stem cell tyrosine kinase 1, the human homolog ofmurine Flk2/Flt3, from a CD34+ hematopoietic stem cell-enriched library.The cDNA encoded a protein of 993 amino acids with 85% identity and 92%similarity to the murine homolog. STK1, which is identical to FLT3, is amember of the type III receptor tyrosine kinase family that includesKIT, FMS, and platelet-derived growth factor receptor. STK1 expressionin human blood and marrow is restricted to CD34+ cells, a populationgreatly enriched by stem/progenitor cells. Antisense oligonucleotidesdirected against STK1 sequences inhibited hematopoietic colonyformation, most strongly in long-term bone marrow cultures. The datasuggested that STK1 may function as a growth factor receptor onhematopoietic stem and/or progenitor cells (OMIM MIM Number: 136351:Mar. 3, 2005).

Levis et al., state that Internal tandem duplication (ITD) mutations ofthe receptor tyrosine kinase FLT3 have been found in 20% to 30% ofpatients with acute myeloid leukemia (AML). These mutationsconstitutively activate the receptor and appear to be associated with apoor prognosis. In their study, dose-response cytotoxic assays wereperformed with AG1295, a tyrosine kinase inhibitor active against FLT3,on primary blasts from patients with AML, and they found that AG1295 wasspecifically cytotoxic to AML blasts harboring FLT3/ITD mutations. Theysuggest that these mutations contribute to the leukemic process and thatthe FLT3 receptor represents a therapeutic target in AML (Levis et al.,Blood 2001, 98:885-887). An Flt3 inhibitor may be useful in treatingacute myeloid leukemia, myelodysplastic syndrome, acute lymphoblasticleukemia.

TrkA:

Target kinase TrkA (i.e., neurotrophic tyrosine kinase, receptor,type 1) is a 140 kDa tyrosine kinase encoded by chromosome 1q21-q22(symbol: NTRK1). TrkA inhibitors may be useful in treating pain (e.g.chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lungcancer, myeloid leukemia, pancreatic cancer), allergic disorders (e.g.asthma), arthritis, diabetic retinopathy, macular degeneration andpsoriasis.

TrkA is a plasma member receptor composed of an extracellular domain(responsible for high affinity binding to nerve growth factor, NGF), atransmembrane segment and an intracellular protein tyrosine kinasedomain (responsible to transmit the NGF signal to initiate andcoordinate neuronal responses). NGF binding induces TrkA clustering onthe membrane and activates the kinase. The kinase initiates a cascade ofprotein phosphorylation events through multiple pathways includingSHC/Ras/MAPK, PI3K and PLCg1. A TrkA kinase inhibitor would not beexpected to prevent NGF/TrkA binding, but could prevent down-streamsignal transduction.

Nerve Growth Factor (NGF) is produced by a number of tissues andinflammatory cells during tissue injury and host immune response. Itinitiates and maintains hypersensitivity to incoming stimulus(hyperalgesia) and the perception of non-noxious stimuli (allodynia).Through its high-affinity receptor TrkA, NGF increases the excitationstate of sensory neurons leading to the central nervous system(peripheral sensitization), and increases transmitter release from thedorsal spinal cord (central sensitization). In clinical trials, a singleNGF subcutaneous injection generated local hyperalgesia persisting up to7 weeks. At doses above 0.1 microgram/kg, NGF caused muscle pain thatvaried from mild to moderate, primarily in the bulbar and truncalmusculature. Intravenous NGF produced earlier and more pronouncedsystemic effects (Petty et al, 1994, Ann Neurol. 36: 244-6). Conversely,TrkA kinase inhibitors could be used to treat diseases of enhancedstates of nociception.

In Complete Freund's Adjuvant (CFA)-induced hind-paw inflammation,spinal nerve ligation and streptozoticin-induced neuropathic painmodels, a single intraperitoneal injection of anti-NGF reversedestablished tactile allodynia from day 3 to day 7 following treatment.In the mouse CCI model, anti-NGF reversed tactile allodynia whenadministered 2 weeks after surgery. Repeated administration of thisantibody to CCI mice for 3 weeks produced a sustained reversal oftactile allodynia (Wild et al, 2007, J. Pharmacol. Exp. Ther.322:282-287).

Prostate tumors that have metastasized to bone frequently induce bonepain which can be difficult to fully control as it seems to be drivensimultaneously by inflammatory, neuropathic, and tumorigenic mechanisms.Anti-NGF produced a significant reduction in both early and late stagebone cancer pain-related behaviors. This therapy did not influencetumor-induced bone remodeling, osteoblast proliferation,osteoclastogenesis, tumor growth, or markers of sensory or sympatheticinnervation in the skin or bone. All nerve fibers that innervate thebone express TrkA and p75, and these are the receptors through which NGFsensitizes and/or activates nociceptors (Halvorson et al, 2005, CancerRes. 65:9426-35).

In patients with mild asthma due to exposure to cat allergen, NGFexpression was strongly induced in epithelial cells, fibroblasts, bloodvessels, and a few infiltrating cells. TrkA mRNA and protein levels inbronchial biopsies were increased significantly after allergen exposurein infiltrating mast cells before the onset of symptoms (Kassel et al,2001, Clin Exp Allergy 31:1432-40).

The late phase reaction in asthma following allergen provocation isdominated by an influx of activated eosinophils into the bronchiallumen, which correlates with the release of eosinophilic products intothe airways to increase disease severity. The viability and activationof eosinophils from patients with mild asthma were significantlyenhanced after NGF stimulation. Addition of neutralizing anti-NGFantibodies ex vivo abrogated the effects (Nassentein et al, 2003, J ExpMed 198:455-467). TrkA kinase inhibitors could decrease this paracrineloop between the respiratory tract and infiltrating mast cells as wellas endobronchial eosinophils, and thus be useful for the treatment ofasthma and other allergic disorders.

TrkB:

Target kinase TrkB (i.e., neurotrophic tyrosine kinase, receptor, type2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22.1 (symbol:NTRK2). TrkB inhibitors may be useful in treating various cancers andtheir metastases (e.g. prostate cancer, lung cancer, Wilms tumors,neuroblastoma, and pancreatic cancer), and various neuropathies (e.g.stroke, multiple sclerosis, transverse myelitis, and encephalitis).

In clinical trials with recombinant BDNF, paresthesia was developed atthe site of subcutaneous injection (Coulie et al, 2000, Gastroenterology119:41-50). Intrathecal infusion of BDNF in humans also inducedparesthesia and warmth as side effects (Ochs et al, 2000, AmyotrophLateral Scler Other Motor Neuron Disord. 1:201-6). Chronic paresthesiais often a symptom of an underlying neurological disease or traumaticnerve damage. Paresthesia can be caused by disorders affecting thecentral nervous system, such as stroke and transient ischemic attacks(mini-strokes), multiple sclerosis, transverse myelitis, andencephalitis. Since BDNF binds to TrkB specifically with high affinitythese neuropath effects are mediated through TrkB signaling. Thus Trkbkinase inhibitors could be used to treat certain patients withneuropathy.

BDNF is known to act at the synapses between primary sensory and spinaldorsal horn neurons to affect pain transmission during inflammation. Theprimary afferent is the only source of BDNF in the spinal cord, and itis up-regulated in the dorsal root ganglion (DRG) by peripheral NGF afew days after inflammation, and is transported and released into thesuperficial dorsal horn in an activity-dependent manner. TrkB expressionin the dorsal horn also increases for a few days after inflammation.These findings suggest that BDNF may act during the restricted period inthe early phase of inflammation. Through TrkB, BDNF activates twodistinct channels: (1) transient receptor potential canonicals (TRPC3),which produces a slow response by opening of a non-selective cationchannel; and (2) Na+ channel, which mediates a rapid depolarization inthe hippocampus. These channels have been strongly associated withinflammatory pain. Anti-BDNF significantly increased the withdrawalthreshold in CFA-treated rats, a model of inflammatory pain. Since theswelling at the site of CFA injection was not affected by antiserum, theresidual component might be due to peripheral sensitization (Matayoshiet al, 2005, J Physiol. 569:685-95).

In patients with neuroblastomas, co-expression of TrkB and BDNF,co-expression of TrkB with N-Myc amplification, and expression oftruncated TrkB are found to be associated with poorer clinical outcome(Nakagawara et al, 1994, Mol Cell Biol. 14:759-767). Co-expression ofTrkB with its ligand BDNF could generate a positive feedback loopthrough autocrine and paracrine loops. Also TrkB truncations found inthese tumors generate activated forms of the intracellular proteintyrosine kinase. The constitutively active TrkB signals through multiplepathways to promote cancer initiation, progression and metastasis. Thesetruncated TrkB kinases were also found in hepatocellular carcinoma (Yanget al, 2005, Cancer. Res 65:219-225). Thus TrkB inhibitors could be usedto treat a sub-population of cancer patients with an activated TrkBpathway.

In patients with pancreatic cancer, TrkB expression is correlated withperineural invasion, positive retroperitoneal margin, and shorterlatency to development of liver metastasis (Sclabas et al, 2005, Clin.Cancer. Res V11:440-449). Mechanistically, TrkB activates the PI3Kpathway to suppress anoikis (apoptosis resulting from loss ofcell-matrix interactions) which is one of the physiological barriers tometastasis. TrkB kinase inhibition could break down resistance toanoikis of metastasizing tumors (Douma et al, 2004, Nature 430:1034-9).Therefore, TrkB inhibitors could have utility in a broad range of tumortypes.

TrkC:

Target kinase TrkC (i.e., neurotrophic tyrosine kinase, receptor, type3) is a 145 kDa tyrosine kinase encoded by chromosome 15q25 (symbol:NTRK3). TrkC inhibitors may be useful in treating pain (e.g. chronicpain, neuropathic pain), cancer (e.g. lung cancer, breast cancer,pancreatic cancer, mesoblastic nephroma, infantile fibrosarcoma,neuroblastoma, gastric cancer), and panic disorder.

Involvement of TrkC in the molecular and cellular changes underlyingpanic attacks and opiate dependence has been indicated (Gallego et al.,Front Behav. Neurosci., 2010, 3:60). TrkC expression in mechanosensoryneurons suggests a role for TrkC inhibition in treatment of pain (JComp. Neurol., 2008, 511(4):543-56.

TrkC is also involved in a variety of cancers, for example neuroblastoma(J. Clin. Invest., 2010, 120(3):850-8), mesoblastic nephroma, infantilefibrosarcoma, and secretory breast cancer, where ETV6-NTRK3 gene fusionis present (Pediatr. Radiol. 2009, 39(10):1066-74; J. Clin. Pathol.2009, 62(7):604-12) and cancers involving mutations in TrkC, such aslung cancer, gastric cancer, and pancreatic cancer (Marchetti et al.,Hum. Mutat. 2008, 29(5):609-16; Kubo et al., Carcinogenesis, 2009,30(11):1857-64); and Kubo et al., Pancreas, 2009, 38(7):e200-6).

Kinase Activity Assays

A number of different assays for kinase activity can be utilized forassaying for active modulators and/or determining specificity of amodulator for a particular kinase or group or kinases. In addition tothe assay mentioned in the Examples below, one of ordinary skill in theart will know of other assays that can be utilized and can modify anassay for a particular application. For example, numerous papersconcerning kinases describe assays that can be used.

Additional alternative assays can employ binding determinations. Forexample, this sort of assay can be formatted either in a fluorescenceresonance energy transfer (FRET) format, or using an AlphaScreen(amplified luminescent proximity homogeneous assay) format by varyingthe donor and acceptor reagents that are attached to streptavidin or thephosphor-specific antibody.

Organic Synthetic Techniques

A wide array of organic synthetic techniques exist in the art tofacilitate the construction of potential modulators. Many of theseorganic synthetic methods are described in detail in standard referencesources utilized by those skilled in the art. One example of such areference is March, 1994, Advanced Organic Chemistry; Reactions,Mechanisms and Structure, New York, McGraw Hill. Thus, the techniquesuseful to synthesize a potential modulator of kinase function arereadily available to those skilled in the art of organic chemicalsynthesis.

Alternative Compound Forms or Derivatives

Compounds contemplated herein are described with reference to bothgeneric formulae and specific compounds. In addition, inventioncompounds may exist in a number of different forms or derivatives, allwithin the scope of the present invention. Alternative forms orderivatives, include, for example, (a) prodrugs, and active metabolites(b) tautomers, isomers (including stereoisomers and regioisomers), andracemic mixtures (c) pharmaceutically acceptable salts and (d) solidforms, including different crystal forms, polymorphic or amorphoussolids, including hydrates and solvates thereof, and other forms.

(a) Prodrugs and Metabolites

In addition to the present formulae and compounds described herein, theinvention also includes prodrugs (generally pharmaceutically acceptableprodrugs), active metabolic derivatives (active metabolites), and theirpharmaceutically acceptable salts.

Prodrugs are compounds or pharmaceutically acceptable salts thereofwhich, when metabolized under physiological conditions or when convertedby solvolysis, yield the desired active compound. Prodrugs include,without limitation, esters, amides, carbamates, carbonates, ureides,solvates, or hydrates of the active compound. Typically, the prodrug isinactive, or less active than the active compound, but may provide oneor more advantageous handling, administration, and/or metabolicproperties. For example, some prodrugs are esters of the activecompound; during metabolysis, the ester group is cleaved to yield theactive drug. Esters include, for example, esters of a carboxylic acidgroup, or S-acyl or O-acyl derivatives of thiol, alcohol, or phenolgroups. In this context, a common example is an alkyl ester of acarboxylic acid. Prodrugs may also include variants wherein an —NH groupof the compound has undergone acylation, such as the 1-position of the1H-pyrrolo[2,3-b]pyridine ring or the 7-position of the7H-pyrrolo[2,3-d]pyrimidine of compounds of Formula I, where cleavage ofthe acyl group provides the free —NH group of the active drug. Someprodrugs are activated enzymatically to yield the active compound, or acompound may undergo further chemical reaction to yield the activecompound. Prodrugs may proceed from prodrug form to active form in asingle step or may have one or more intermediate forms which maythemselves have activity or may be inactive.

As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed.Wermuth, Academic Press, San Diego, Calif., 2001), prodrugs can beconceptually divided into two non-exclusive categories, bioprecursorprodrugs and carrier prodrugs. Generally, bioprecursor prodrugs arecompounds that are inactive or have low activity compared to thecorresponding active drug compound, that contain one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollowing types:

Oxidative Reactions:

Oxidative reactions are exemplified without limitation by reactions suchas oxidation of alcohol, carbonyl, and acid functionalities,hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbonatoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbondouble bonds, oxidation of nitrogen-containing functional groups,oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative 0- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

Reductive Reactions:

Reductive reactions are exemplified without limitation by reactions suchas reduction of carbonyl functionalities, reduction of alcoholfunctionalities and carbon-carbon double bonds, reduction ofnitrogen-containing functional groups, and other reduction reactions.

Reactions without Change in the Oxidation State:

Reactions without change in the state of oxidation are exemplifiedwithout limitation by reactions such as hydrolysis of esters and ethers,hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavageof non-aromatic heterocycles, hydration and dehydration at multiplebonds, new atomic linkages resulting from dehydration reactions,hydrolytic dehalogenation, removal of hydrogen halide molecule, andother such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improves uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, the prodrug and anyrelease transport moiety are acceptably non-toxic. For prodrugs wherethe transport moiety is intended to enhance uptake, typically therelease of the transport moiety should be rapid. In other cases, it isdesirable to utilize a moiety that provides slow release, e.g., certainpolymers or other moieties, such as cyclodextrins. (See, e.g., Cheng etal., U.S. Patent Publ. No. 20040077595, application Ser. No. 10/656,838,incorporated herein by reference.) Such carrier prodrugs are oftenadvantageous for orally administered drugs. In some instances, thetransport moiety provides targeted delivery of the drug, for example thedrug may be conjugated to an antibody or antibody fragment. Carrierprodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, supra.

Metabolites, e.g., active metabolites, overlap with prodrugs asdescribed above, e.g., bioprecursor prodrugs. Thus, such metabolites arepharmacologically active compounds or compounds that further metabolizeto pharmacologically active compounds that are derivatives resultingfrom metabolic processes in the body of a subject. Of these, activemetabolites are such pharmacologically active derivative compounds. Forprodrugs, the prodrug compound is generally inactive or of loweractivity than the metabolic product. For active metabolites, the parentcompound may be either an active compound or may be an inactive prodrug.For example, in some compounds, one or more alkoxy groups can bemetabolized to hydroxyl groups while retaining pharmacologic activityand/or carboxyl groups can be esterified, e.g., glucuronidation. In somecases, there can be more than one metabolite, where an intermediatemetabolite(s) is further metabolized to provide an active metabolite.For example, in some cases a derivative compound resulting frommetabolic glucuronidation may be inactive or of low activity, and can befurther metabolized to provide an active metabolite.

Metabolites of a compound may be identified using routine techniquesknown in the art, and their activities determined using tests such asthose described herein. See, e.g., Bertolini et al., 1997, J. Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757;Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.

(b) Tautomers, Stereoisomers, and Regioisomers

It is understood that some compounds may exhibit tautomerism. In suchcases, the formulae provided herein expressly depict only one of thepossible tautomeric forms. It is therefore to be understood that theformulae provided herein are intended to represent any tautomeric formof the depicted compounds and are not to be limited merely to thespecific tautomeric form depicted by the drawings of the formulae.

Likewise, some of the compounds according to the present invention mayexist as stereoisomers, i.e. having the same atomic connectivity ofcovalently bonded atoms yet differing in the spatial orientation of theatoms. For example, compounds may be optical stereoisomers, whichcontain one or more chiral centers, and therefore, may exist in two ormore stereoisomeric forms (e.g. enantiomers or diastereomers). Thus,such compounds may be present as single stereoisomers (i.e., essentiallyfree of other stereoisomers), racemates, and/or mixtures of enantiomersand/or diastereomers. As another example, stereoisomers includegeometric isomers, such as cis- or trans-orientation of substituents onadjacent carbons of a double bond, or on carbon atoms of a cycloalkyl.All such single stereoisomers, racemates and mixtures thereof areintended to be within the scope of the present invention. Unlessspecified to the contrary, all such stereoisomeric forms are includedwithin the formulae provided herein.

In some embodiments, a chiral compound of the present invention is in aform that contains at least 80% of a single isomer (60% enantiomericexcess (“e.e.”) or diastereomeric excess (“d.e.”)), or at least 85% (70%e.e. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.), 97.5%(95% e.e. or d.e.), or 99% (98% e.e. or d.e.). As generally understoodby those skilled in the art, an optically pure compound having onechiral center is one that consists essentially of one of the twopossible enantiomers (i.e., is enantiomerically pure), and an opticallypure compound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. In some embodiments,the compound is present in optically pure form, such optically pure formbeing prepared and/or isolated by methods known in the art (e.g. byrecrystallization techniques, chiral synthetic techniques (includingsynthesis from optically pure starting materials), and chromatographicseparation using a chiral column.

(c) Pharmaceutically Acceptable Salts

Unless specified to the contrary, specification of a compound hereinincludes pharmaceutically acceptable salts of such compound. Thus,compounds of Formula I can be in the form of pharmaceutically acceptablesalts, or can be formulated as pharmaceutically acceptable salts.Contemplated pharmaceutically acceptable salt forms include, withoutlimitation, mono, bis, tris, tetrakis, and so on. Pharmaceuticallyacceptable salts are non-toxic in the amounts and concentrations atwhich they are administered. The preparation of such salts canfacilitate the pharmacological use by altering the physicalcharacteristics of a compound without preventing it from exerting itsphysiological effect. Useful alterations in physical properties includelowering the melting point to facilitate transmucosal administration andincreasing the solubility to facilitate administering higherconcentrations of the drug. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly can react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

Pharmaceutically acceptable salts include acid addition salts such asthose containing chloride, bromide, iodide, hydrochloride, acetate,phenylacetate, acrylate, ascorbate, aspartate, benzoate,2-phenoxybenzoate, 2-acetoxybenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, methylbenzoate, bicarbonate, butyne-1,4 dioate,hexyne-1,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate,citrate, decanoate, formate, fumarate, glycolate, gluconate, glucarate,glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate,isethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,lactate, malate, maleate, hydroxymaleate, methylmaleate, malonate,mandelate, nicotinate, nitrate, isonicotinate, octanoate, oleate,oxalate, pamoate, phosphate, monohydrogenphosphate, dihydrogenphosphate,orthophosphate, metaphosphate, pyrophosphate, 2-phosphoglycerate,3-phosphoglycerate, phthalate, propionate, phenylpropionate, propiolate,pyruvate, quinate, salicylate, 4-aminosalicylate, sebacate, stearate,suberate, succinate, sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, sulfamate, sulfonate, benzenesulfonate (i.e. besylate),ethanesulfonate (i.e. esylate), ethane-1,2-disulfonate,2-hydroxyethanesulfonate (i.e. isethionate), methanesulfonate (i.e.mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate (i.e.napsylate), propanesulfonate, p-toluenesulfonate (i.e. tosylate),xylenesulfonates, cyclohexylsulfamate, tartrate, and trifluoroacetate.These pharmaceutically acceptable acid addition salts can be preparedusing the appropriate corresponding acid.

When acidic functional groups, such as carboxylic acid or phenol arepresent, pharmaceutically acceptable salts also include basic additionsalts such as those containing benzathine, chloroprocaine, choline,ethanolamine, diethanolamine, triethanolamine, t-butylamine,dicyclohexylamine, ethylenediamine, N,N′-dibenzylethylenediamine,meglumine, hydroxyethylpyrrolidine, piperidine, morpholine, piperazine,procaine, aluminum, calcium, copper, iron, lithium, magnesium,manganese, potassium, sodium, zinc, ammonium, and mono-, di-, ortri-alkylamines (e.g. diethylamine), or salts derived from amino acidssuch as L-histidine, L-glycine, L-lysine, and L-arginine. For example,see Remington's Pharmaceutical Sciences, 19^(th) ed., Mack PublishingCo., Easton, Pa., Vol. 2, p. 1457, 1995. These pharmaceuticallyacceptable base addition salts can be prepared using the appropriatecorresponding base.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound can bedissolved in a suitable solvent, such as an aqueous or aqueous-alcoholsolution containing the appropriate acid and then isolated byevaporating the solution. In another example, a salt can be prepared byreacting the free base and acid in an organic solvent. If the particularcompound is an acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an appropriate inorganic or organic base.

(d) Other Compound Forms

In the case of agents that are solids, it is understood by those skilledin the art that the compounds and salts may exist in different crystalor polymorphic forms, or may be formulated as co-crystals, or may be inan amorphous form, or may be any combination thereof (e.g. partiallycrystalline, partially amorphous, or mixtures of polymorphs) all ofwhich are intended to be within the scope of the present invention andspecified formulae. Whereas salts are formed by acid/base addition, i.e.a free base or free acid of the compound of interest forms an acid/basereaction with a corresponding addition base or addition acid,respectively, resulting in an ionic charge interaction, co-crystals area new chemical species that is formed between neutral compounds,resulting in the compound and an additional molecular species in thesame crystal structure.

In some instances, compounds of the invention are complexed with an acidor a base, including base addition salts such as ammonium, diethylamine,ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine,meglumine; acid addition salts, such as acetate, acetylsalicylate,besylate, camsylate, citrate, formate, fumarate, glutarate,hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate,succinate, sulfate, tartrate, thiocyanate and tosylate; and amino acidssuch as alanine, arginine, asparagine, aspartic acid, cysteine,glutamine, glutamic acid, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine or valine. In combining the compound of theinvention with the acid or base, an amorphous complex is preferablyformed rather than a crystalline material such as a typical salt orco-crystal. In some instances, the amorphous form of the complex isfacilitated by additional processing, such as by spray-drying,mechanochemical methods such as roller compaction, or microwaveirradiation of the parent compound mixed with the acid or base. Suchmethods may also include addition of ionic and/or non-ionic polymersystems, including, but not limited to, hydroxypropyl methyl celluloseacetate succinate (HPMCAS) and methacrylic acid copolymer (e.g.Eudragit® L100-55), that further stabilize the amorphous nature of thecomplex. Such amorphous complexes provide several advantages. Forexample, lowering of the melting temperature relative to the free basefacilitates additional processing, such as hot melt extrusion, tofurther improve the biopharmaceutical properties of the compound. Also,the amorphous complex is readily friable, which provides improvedcompression for loading of the solid into capsule or tablet form.

Additionally, the formulae are intended to cover hydrated or solvated aswell as unhydrated or unsolvated forms of the identified structures. Forexample, the indicated compounds include both hydrated and non-hydratedforms. Other examples of solvates include the structures in combinationwith a suitable solvent, such as isopropanol, ethanol, methanol,dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine.

Formulations and Administration

The methods and compounds will typically be used in therapy for humansubjects. However, they may also be used to treat similar or identicalindications in other animal subjects. Compounds of Formula I or any ofthe subformulas as described herein, or any of the compounds disclosedin any of the embodiments and examples, and pharmaceutically acceptablesalts or solvates thereof can be administered by different routes,including injection (i.e. parenteral, including intravenous,intraperitoneal, subcutaneous, and intramuscular), oral, transdermal,transmucosal, rectal, or inhalant. Such dosage forms should allow thecompound to reach target cells. Other factors are well known in the art,and include considerations such as toxicity and dosage forms that retardthe compound or composition from exerting its effects. Techniques andformulations generally may be found in Remington: The Science andPractice of Pharmacy, 21^(st) edition, Lippincott, Williams and Wilkins,Philadelphia, Pa., 2005 (hereby incorporated by reference herein).

In some embodiments, compositions will comprise pharmaceuticallyacceptable carriers or excipients, such as fillers, binders,disintegrants, glidants, lubricants, complexing agents, solubilizers,and surfactants, which may be chosen to facilitate administration of thecompound by a particular route. Examples of carriers include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, types of starch, cellulose derivatives, gelatin, lipids,liposomes, nanoparticles, and the like. Carriers also includephysiologically compatible liquids as solvents or for suspensions,including, for example, sterile solutions of water for injection (WFI),saline solution, dextrose solution, Hank's solution, Ringer's solution,vegetable oils, mineral oils, animal oils, polyethylene glycols, liquidparaffin, and the like. Excipients may also include, for example,colloidal silicon dioxide, silica gel, talc, magnesium silicate, calciumsilicate, sodium aluminosilicate, magnesium tri silicate, powderedcellulose, macrocrystalline cellulose, carboxymethyl cellulose,cross-linked sodium carboxymethylcellulose, sodium benzoate, calciumcarbonate, magnesium carbonate, stearic acid, aluminum stearate, calciumstearate, magnesium stearate, zinc stearate, sodium stearyl fumarate,syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate,glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate,hydrogenated vegetable oil, hydrogenated cotton seed oil, castor seedoil mineral oil, polyethylene glycol (e.g. PEG 4000-8000),polyoxyethylene glycol, poloxamers, povidone, crospovidone,croscarmellose sodium, alginic acid, casein, methacrylic aciddivinylbenzene copolymer, sodium docusate, cyclodextrins (e.g.2-hydroxypropyl-.delta.-cyclodextrin), polysorbates (e.g. polysorbate80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000succinate), magnesium lauryl sulfate, sodium lauryl sulfate,polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols,or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylenesorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters,sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fattyacid such as oleic, stearic or palmitic acid, mannitol, xylitol,sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried,sucrose, fructose, calcium phosphate, dibasic calcium phosphate,tribasic calcium phosphate, calcium sulfate, dextrates, dextran,dextrin, dextrose, cellulose acetate, maltodextrin, simethicone,polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcelluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose,hypromellose, and the like.

In some embodiments, oral administration may be used. Pharmaceuticalpreparations for oral use can be formulated into conventional oraldosage forms such as capsules, tablets, and liquid preparations such assyrups, elixirs, and concentrated drops. Compounds of Formula I may becombined with solid excipients, optionally grinding a resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain, for example, tablets, coatedtablets, hard capsules, soft capsules, solutions (e.g. aqueous,alcoholic, or oily solutions) and the like. Suitable excipients are, inparticular, fillers such as sugars, including lactose, glucose, sucrose,mannitol, or sorbitol; cellulose preparations, for example, corn starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:povidone); oily excipients, including vegetable and animal oils, such assunflower oil, olive oil, or codliver oil. The oral dosage formulationsmay also contain disintegrating agents, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such assodium alginate; a lubricant, such as talc or magnesium stearate; aplasticizer, such as glycerol or sorbitol; a sweetening such as sucrose,fructose, lactose, or aspartame; a natural or artificial flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring; ordye-stuffs or pigments, which may be used for identification orcharacterization of different doses or combinations. Also provided aredragee cores with suitable coatings. For this purpose, concentratedsugar solutions may be used, which may optionally contain, for example,gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the invention(as a free-base, solvate (including hydrate) or salt, in any form),depending on the condition being treated, the route of administration,and the age, weight and condition of the patient. Preferred unit dosageformulations are those containing a daily dose, weekly dose, monthlydose, a sub-dose or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical formulations may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin (“gelcaps”), as well as soft, sealed capsulesmade of gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols.

In some embodiments, injection (parenteral administration) may be used,e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous.Compounds of Formula I for injection may be formulated in sterile liquidsolutions, preferably in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. Dispersions may also be prepared in non-aqueous solutions,such as glycerol, propylene glycol, ethanol, liquid polyethyleneglycols, triacetin, and vegetable oils. Solutions may also contain apreservative, such as methylparaben, propylparaben, chlorobutanol,phenol, sorbic acid, thimerosal, and the like. In addition, thecompounds may be formulated in solid form, including, for example,lyophilized forms, and redissolved or suspended prior to use.

In some embodiments, transmucosal, topical or transdermal administrationmay be used. In such formulations of compounds of Formula I, penetrantsappropriate to the barrier to be permeated are used. Such penetrants aregenerally known in the art, and include, for example, for transmucosaladministration, bile salts and fusidic acid derivatives. In addition,detergents may be used to facilitate permeation. Transmucosaladministration, for example, may be through nasal sprays orsuppositories (rectal or vaginal). Compositions of compounds of FormulaI for topical administration may be formulated as oils, creams, lotions,ointments, and the like by choice of appropriate carriers known in theart. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). In someembodiments, carriers are selected such that the active ingredient issoluble. Emulsifiers, stabilizers, humectants and antioxidants may alsobe included as well as agents imparting color or fragrance, if desired.Creams for topical application are preferably formulated from a mixtureof mineral oil, self-emulsifying beeswax and water in which mixture theactive ingredient, dissolved in a small amount of solvent (e.g., anoil), is admixed. Additionally, administration by transdermal means maycomprise a transdermal patch or dressing such as a bandage impregnatedwith an active ingredient and optionally one or more carriers ordiluents known in the art. To be administered in the form of atransdermal delivery system, the dosage administration will becontinuous rather than intermittent throughout the dosage regimen.

In some embodiments, compounds are administered as inhalants. Compoundsof Formula I may be formulated as dry powder or a suitable solution,suspension, or aerosol. Powders and solutions may be formulated withsuitable additives known in the art. For example, powders may include asuitable powder base such as lactose or starch, and solutions maycomprise propylene glycol, sterile water, ethanol, sodium chloride andother additives, such as acid, alkali and buffer salts. Such solutionsor suspensions may be administered by inhaling via spray, pump,atomizer, or nebulizer, and the like. The compounds of Formula I mayalso be used in combination with other inhaled therapies, for examplecorticosteroids such as fluticasone proprionate, beclomethasonedipropionate, triamcinolone acetonide, budesonide, and mometasonefuroate; beta agonists such as albuterol, salmeterol, and formoterol;anticholinergic agents such as ipratroprium bromide or tiotropium;vasodilators such as treprostinal and iloprost; enzymes such as DNAase;therapeutic proteins; immunoglobulin antibodies; an oligonucleotide,such as single or double stranded DNA or RNA, siRNA; antibiotics such astobramycin; muscarinic receptor antagonists; leukotriene antagonists;cytokine antagonists; protease inhibitors; cromolyn sodium; nedocrilsodium; and sodium cromoglycate.

The amounts of various compounds to be administered can be determined bystandard procedures taking into account factors such as the compoundactivity (in vitro, e.g. the compound IC₅₀ vs. target, or in vivoactivity in animal efficacy models), pharmacokinetic results in animalmodels (e.g. biological half-life or bioavailability), the age, size,and weight of the subject, and the disorder associated with the subject.The importance of these and other factors are well known to those ofordinary skill in the art. Generally, a dose will be in the range ofabout 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject beingtreated. Multiple doses may be used.

The compounds of Formula I may also be used in combination with othertherapies for treating the same disease. Such combination use includesadministration of the compounds and one or more other therapeutics atdifferent times, or co-administration of the compound and one or moreother therapies. In some embodiments, dosage may be modified for one ormore of the compounds of the invention or other therapeutics used incombination, e.g., reduction in the amount dosed relative to a compoundor therapy used alone, by methods well known to those of ordinary skillin the art.

It is understood that use in combination includes use with othertherapies, drugs, medical procedures etc., where the other therapy orprocedure may be administered at different times (e.g. within a shorttime, such as within hours (e.g. 1, 2, 3, 4-24 hours), or within alonger time (e.g. 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)) than acompound of Formula I, or at the same time as a compound of Formula I.Use in combination also includes use with a therapy or medical procedurethat is administered once or infrequently, such as surgery, along with acompound of Formula I administered within a short time or longer timebefore or after the other therapy or procedure. In some embodiments, thepresent invention provides for delivery of a compound of Formula I andone or more other drug therapeutics delivered by a different route ofadministration or by the same route of administration. The use incombination for any route of administration includes delivery of acompound of Formula I and one or more other drug therapeutics deliveredby the same route of administration together in any formulation,including formulations where the two compounds are chemically linked insuch a way that they maintain their therapeutic activity whenadministered. In one aspect, the other drug therapy may beco-administered with a compound of Formula I. Use in combination byco-administration includes administration of co-formulations orformulations of chemically joined compounds, or administration of two ormore compounds in separate formulations within a short time of eachother (e.g. within an hour, 2 hours, 3 hours, up to 24 hours),administered by the same or different routes. Co-administration ofseparate formulations includes co-administration by delivery via onedevice, for example the same inhalant device, the same syringe, etc., oradministration from separate devices within a short time of each other.Co-formulations of a compound of Formula I and one or more additionaldrug therapies delivered by the same route includes preparation of thematerials together such that they can be administered by one device,including the separate compounds combined in one formulation, orcompounds that are modified such that they are chemically joined, yetstill maintain their biological activity. Such chemically joinedcompounds may have a linkage that is substantially maintained in vivo,or the linkage may break down in vivo, separating the two activecomponents.

EXAMPLES

Examples related to the present invention are described below. In mostcases, alternative techniques can be used. The examples are intended tobe illustrative and are not limiting or restrictive to the scope of theinvention. For example, where additional compounds are preparedfollowing a protocol of a Scheme for a particular compound, it isunderstood that conditions may vary, for example, any of the solvents,reaction times, reagents, temperatures, work up conditions, or otherreaction parameters may be varied employing alternate solvents,reagents, reaction times, temperatures, work up conditions, and thelike, as are readily available to one skilled in the art. In someexamples, the mass spectrometry result indicated for a compound may havemore than one value due to the isotope distribution of an atom in themolecule, such as a compound having a bromo or chloro substituent.

Unless specifically indicated otherwise, the Formula enumeration and Rgroup enumeration used in the following examples is not related to suchenumeration in other sections of this application. The reagents andsolvents used in these examples can be readily substituted withappropriate alternatives as are known in the art and isolation ofproducts is readily achieved by methods known in the art, including, butnot limited to, extraction, crystallization, and chromatographicmethods.

Ring numbering for the 1H-pyrrolo[2,3-b]pyridine in the followingExamples is as follows:

Ring numbering for the 7H-pyrrolo[2,3-d]pyrimidine in the followingExamples is as follows:

Example 1: Synthesis of5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4

5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4 isprepared in two steps from 5-chloro-1H-pyrrolo[2,3-b]pyridine 1 as shownin Scheme 1.

Step 1—Preparation of 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2)

To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (1, 15.00 g, 98.31mmol) in 300 mL of dichloromethane under an atmosphere or nitrogen,pyridine (7.951 mL, 98.31 mmol) and iodine monochloride (110 mL, 1.0 Min dichloromethane, 110 mmol) are added slowly over 20 minutes. Thereaction is stirred at room temperature for 2 hours, then quenched with100 mL of 1 M aqueous sodium thiosulfate pentahydrate. The layers areseparated, solids collected from the aqueous layer by filtration andcombined with the organic layer. The aqueous layer is extracted withethyl acetate, and the organic layers are combined and washed withbrine, then concentrated under vacuum. The resulting solid is washedwith 20% ethyl acetate in hexane to provide the desired compound.

Step 2—Preparation of5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (4)

To 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2, 16.50 g, 59.25 mmol) in250.0 mL of N,N-dimethylformamide, sodium hydride (3.10 g, 77.5 mmol) isadded. The reaction is stirred at room temperature for 90 minutes, thentriisopropylsilyl chloride (3, 13.00 mL, 61.36 mmol) is added slowly.The reaction is stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer is dried oversodium sulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fractions arecombined and concentrated under vacuum to provide the desired compound(4, 10.0 g).

Example 2: Synthesis of 3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 7

3-Iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 7 is prepared in two stepsfrom 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 5 as shownin Scheme 2.

Step 1—Preparation of5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6)

In a round bottom flask, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.04 g, 0.05mmol) is combined with 10 mL of toluene under an atmosphere of nitrogen,and 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (5, 0.3 g,0.8 mmol) in 1 mL of toluene is added dropwise. The reaction is stirredat 60° C. for 1 hour, then at 90° C. for 30 minutes. The reaction iscooled to room temperature, an ice/water solution of 0.1 N citric acidat pH 4 is added, and the mixture extracted with ethyl acetate. Theorganic layer is washed with brine, de-colored with charcoal, filteredthrough celite and the filtrate dried over sodium sulfate. The sodiumsulfate is removed by filtration and the filtrate concentrated undervacuum to provide the desired compound (6, 218 mg).

Step 2—Preparation of 3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine (7)

To a solution of5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 1 g, 2.0mmol) in 10 mL of tetrahydrofuran, iodine (0.43 g, 1.7 mmol) in 5 mL oftetrahydrofuran is added. The reaction is stirred at room temperatureovernight, then quenched with 20 mL of 1M aqueous sodium thiosulfate andextracted with ethyl acetate. The organic layers are combined and washedwith water and brine, dried over sodium sulfate, filtered and thefiltrate concentrated under vacuum. The resulting material is purifiedby silica gel column chromatography, eluting with ethyl acetate andhexanes. Appropriate fractions are combined and concentrated undervacuum to provide the desired compound as a white solid (7, 20 mg). MS(ESI) [M+H⁺]⁺=258.70.

Example 3: Synthesis of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8

3-Iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 isprepared in one step from5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 6 as shown inScheme 3.

Step 1—Preparation of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8)

5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (6, 1.1 g, 3.8mmol) and 10 mL of dichloromethane are combined in a round bottom flaskand stirred for 10 minutes. A slurry of N-iodosuccinimide (1.0 g, 4.6mmol) in 5 mL of dichloromethane is added and stirred at roomtemperature overnight. The reaction is quenched with sodium thiosulfate(20 mL, 1M in water) and the aqueous layer is extracted with ethylacetate. The combined organic layer is washed with water and brine,dried with sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is purified by silica gel columnchromatography, eluting with ethyl acetate and hexanes. Appropriatefractions are combined and concentrated under vacuum to provide thedesired compound as a light yellow oil (8, 1.2 g, 75%). MS (ESI)[M+H⁺]⁺=415.08.

Example 4: Synthesis of4-ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 13

4-Ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 13 isprepared in three steps from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 asshown in Scheme 4.

Step 1—Preparation of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (11)

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 300 mg, 1.95 mmol) is combinedwith 3.00 mL of ethanol (10, 51.4 mmol), then potassium hydroxide (0.226g, 4.03 mmol) is added. The reaction is heated at 120° C. for 3 hours ina microwave, then extracted with ethyl acetate and aqueous saturatedammonium chloride. The organic layer is washed with brine, dried withmagnesium sulfate, filtered and the filtrate concentrated under vacuum.The resulting material is recrystallized from methanol to provide thedesired compound (11, 213 mg). MS (ESI) [M+H⁺]⁺=164.9.

Step 2—Preparation of 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12)

To 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (11, 1.60 g, 9.8 mmol) in 50.0mL of dichloromethane, N,N-dimethylformamide (2.0 mL, 26 mmol) andN-iodosuccinimide (2.40 g, 10.7 mmol) are added and the reaction stirredat room temperature for 2 hours. The reaction is poured into water andextracted with ethyl acetate. The organic layer is dried with sodiumsulfate, filtered and the filtrate concentrated under vacuum to providethe desired compound (12, 2.70 g).

Step 3—Preparation of4-ethoxy-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (13)

To 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12, 2.70 g, 9.34 mmol)in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodiumhydride (411.0 mg, 10.27 mmol) is added. The reaction is stirred at roomtemperature for 20 minutes, then triisopropylsilyl chloride (3, 2.177mL, 10.27 mmol) is added. The reaction is stirred at room temperaturefor 2 hours, then poured into water and extracted with ethyl acetate.The organic layer is dried over sodium sulfate, filtered and thefiltrate concentrated under vacuum. The resulting material is purifiedby silica gel column chromatography, eluting with 5-100% ethyl acetatein hexane. Appropriate fractions are combined and concentrated undervacuum to provide the desired compound (13, 3.90 g).

5-Iodo-4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 14

is prepared similarly to the protocol of Scheme 4, replacing ethanolwith methanol in step 1.

5-Iodo-4-methyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 16

is prepared similarly to the protocol of Scheme 4, where step 1 isreplaced by the following step 1a:

Step 1a—Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (15)

To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8 mmol) in 100 mLof toluene, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)1:1 complex with dichloromethane (0.627 g, 0.328 mmol) is added under anatmosphere of nitrogen. After stirring for 10 minutes, methylmagnesiumbromide (62.9 mL, 3.00 M in ether, 189 mmol) is added slowly. Thereaction is heated at 55° C. overnight, then cooled to −70 to −80° C.and quenched by adding ammonium chloride dropwise. Then 1N hydrochloricacid is added and the pH is adjusted to 7-8 with the addition ofsaturated sodium bicarbonate. This is extracted 3× with ethyl acetate.The combined organic layer is washed with saturated ammonium chlorideand brine, then dried with magnesium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography, eluting with ethyl acetate anddichloromethane, then methanol and dichloromethane. Appropriatefractions are combined and concentrated under vacuum to provide thedesired compound as a tan solid (15). MS (ESI) [M+H⁺]⁺=134. This isreacted similarly to steps 2 and 3 of Scheme 4 to provide the desiredcompound 16.

4-Cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine19

is prepared similarly to the protocol of Scheme 4, where step 1 isreplaced by the following step 1b:

Step 1b—Preparation of 4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (18)

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 0.452 g, 2.94 mmol),cyclopropylmagnesium bromide (17, 31.4 mL, 0.50 M in tetrahydrofuran,15.7 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complexwith dichloromethane (0.240 g, 0.294 mmol) are combined with 15.4 mL oftoluene. The reaction is heated at 60° C. overnight, then quenched with1 M aqueous hydrochloric acid to pH 4 and filtered through a bed ofcelite. The layers of the filtrate are separated and the aqueous layerextracted with ethyl acetate. The combined organic layers are washedwith brine, dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography, eluting with ethyl acetate and hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (18, 0.465 g). MS (ESI) [M+H⁺]⁺=160.1. Thisis reacted similarly to steps 2 and 3 of Scheme 4 to provide the desiredcompound 19.

Cyclopropyl-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 22

is prepared similarly to the protocol of scheme 4, steps 1 and 2, wherestep 1 is replaced by the following step 1c:

Step 1c—Preparation ofcyclopropyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (21)

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 1.06 g, 6.90 mmol) is dissolvedin cyclopropylamine (20, 2.42 mL, 34.5 mmol) and heated to refluxovernight. The reaction mixture is cooled and poured into water, thenextracted with ethyl acetate. The organic layer is washed with brine,dried over sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is purified by silica gel columnchromatography, eluting with ethyl acetate and dichloromethane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (21, 337 mg). MS (ESI) [M+H⁺]⁺=174.9. Thisis reacted similarly to step 2 of Scheme 4 to provide the desiredcompound 22.

Example 5: Synthesis of7-benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine27

7-Benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine27 is prepared in three steps from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine9 as shown in Scheme 5.

Step 1—Preparation of 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine(24)

To 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.00 g, 32.6 mmol) in 12.5mL of 2-methoxy-ethanol (23, 158 mmol), potassium hydroxide (3.3 g, 59mmol) is added. The reaction is heated at 100° C. overnight, then pouredinto water and extracted with ethyl acetate. The organic layer is driedwith sodium sulfate, filtered and the filtrate concentrated under vacuumto provide the desired compound (24, 5.70 g).

Step 2—Preparation of5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25)

To 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (24, 5.70 g, 29.5mmol) in 150.0 mL of dichloromethane, N,N-dimethylformamide (6.0 mL, 78mmol) and N-iodosuccinimide (7.22 g, 32.1 mmol) are added and thereaction stirred at room temperature for 2 hours. The reaction is pouredinto water and extracted with ethyl acetate. The organic layer is driedwith sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is washed with ethyl acetate and hexaneto provide the desired compound (25, 6.75 g).

Step 3—Preparation of7-benzenesulfonyl-5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine(27)

To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25, 3.67 g,11.5 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere ofnitrogen, sodium hydride (506.0 mg, 12.65 mmol) is added. The reactionis stirred at room temperature for 20 minutes, then benzenesulfonylchloride (26, 1.614 mL, 12.65 mmol) is added. The reaction is stirred atroom temperature for 30 minutes, then poured into water and extractedwith ethyl acetate. The organic layer is dried over sodium sulfate,filtered and the filtrate concentrated under vacuum. The resultingmaterial is purified by silica gel column chromatography, eluting with15-100% ethyl acetate in hexane. Appropriate fractions are combined andconcentrated under vacuum to provide the desired compound (27, 4.50 g).MS (ESI) [M+H⁺]⁺=460.0.

1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 28,1-benzenesulfonyl-3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 29, and7-benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 30,

are prepared following the protocol of scheme 5 step 3 or steps 2 and 3,replacing 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine 25with 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 and3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 7, respectively in step 3, orby reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 9 directly in step 2.

7-Benzenesulfonyl-5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine 31 and7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 32,

are prepared following the protocol of scheme 5 steps 2 and 3, replacing4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine 24 with4-methyl-7H-pyrrolo[2,3-d]pyrimidine 15 and4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine 18, respectively, in step 2.

4-Cyclopropyl-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine33,

is synthesized similarly to compound 32, where 4-methylbenzenesulfonylchloride is used in place of benzenesulfonyl chloride 26 in step 3 ofScheme 5.

Example 6: Synthesis of1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine37

1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine37 is prepared in three steps from1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 28 and2-methylsulfanyl-pyrimidine-5-carbaldehyde 34 as shown in Scheme 6.

Step 1—Preparation of(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol(35)

To a solution of1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (28, 8.40 g,20.1 mmol) in 96.3 mL of tetrahydrofuran at −40° C. under nitrogen,isopropylmagnesium chloride (10.1 mL, 2.0 M in tetrahydrofuran, 20.3mmol) is added slowly. The reaction is allowed to warm to 5° C. over 60minutes, then cooled to −40° C., followed by addition of2-methylsulfanyl-pyrimidine-5-carbaldehyde (34, 2.50 g, 16.2 mmol) in15.0 mL of tetrahydrofuran. The reaction is allowed to warm to 10° C.over 2 hours, then poured into aqueous ammonium chloride and extractedwith ethyl acetate. The organic layer is dried over sodium sulfate,filtered and the filtrate is concentrated under vacuum. The resultingmaterial is purified by silica gel column chromatography eluting with40-100% ethyl acetate in hexane. Appropriate fractions are combined andthe solvents removed under vacuum to provide the desired compound as anoff-white solid (35, 4.0 g). MS (ESI) [M+H⁺]⁺=447.2.

Step 2—Preparation of1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(36)

To(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-methylsulfanyl-pyrimidin-5-yl)-methanol(35, 4.70 g, 10.5 mmol) in 120.0 mL of acetonitrile, triethylsilane(22.0 mL, 138 mmol) and trifluoroacetic acid (11.0 mL, 143 mmol) areadded. The reaction is stirred at 80° C. for 3 hours, then concentratedunder vacuum, mixed with aqueous potassium carbonate and extracted withethyl acetate. The organic layer is dried over sodium sulfate, filteredand the filtrate concentrated under vacuum. The resulting material ispurified by silica gel column chromatography eluting with 20-100% ethylacetate in hexane. Appropriate fractions are combined and solventsremoved under vacuum to provide the desired compound (36, 2.90 g).

Step 3—Preparation of1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(37)

To1-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(36, 4.40 g, 10.2 mmol) in 100.0 mL of dichloromethane,meta-chloroperoxybenzoic acid (max. 77%, 4.90 g, 21.9 mmol) is added at0° C. The reaction is stirred at 0° C. for 40 minutes, then poured intowater and extracted with ethyl acetate. The organic layer is dried oversodium sulfate, filtered, and the filtrate is concentrated under vacuum.The resulting material is purified by silica gel column chromatographyeluting with 20% ethyl acetate in hexane. Appropriate fractions arecombined and solvents removed under vacuum to provide the desiredcompound (37, 3.76 g). MS (ESI) [M+H⁺]⁺=463.0.

1-Benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine38

is prepared following the protocol of Scheme 6, replacing1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 28 with1-benzenesulfonyl-3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 29 in step1.

Example 7: Synthesis of6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine49

6-fluoro-5-(5-methyl-1H-pyrrolo[2,3]pyridin-3-ylmethyl)-pyridin-2-ylamine49 is prepared in seven steps from 2,6-difluoro-pyridine 39 and4-methoxy-benzylamine 40 as shown in Scheme 7.

Step 1—Preparation of (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine(41)

To 2,6-difluoro-pyridine (39, 100 g, 869 mmol) in 500 mL ofN-methylpyrrolidinone, 4-methoxy-benzylamine (40, 136 mL, 1.043 mol) andN,N-diisopropylethylamine (304 mL, 1.738 mol) are added. The reaction isstirred at 90° C. overnight, then poured into 8 L of water. Theresulting precipitate is collected by filtration and washed with water,then taken up in ethyl acetate and washed with water. The organic layeris dried over sodium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material is triturated with heptane andcollected by filtration to provide the desired compound (41, 151 g, 650mmol, 74.8% yield).

Step 2—Preparation of(5-bromo-6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (42)

To (6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (41, 151 g, 650mmol) in 4 L of acetonitrile under an atmosphere of nitrogen,N-bromosuccinimide (116 g, 650 mmol) is added in portions. Afterreacting for 2 hours, the solvent is removed under vacuum and theresidue is taken up in ethyl acetate, then poured into aqueous sodiumthiosulfate. The organic layer is washed with warm water, dried oversodium sulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is crystallized from heptane to provide the desiredcompound (42, 172 g, 553 mmol, 85% yield).

Step 3—Preparation of 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic acidmethyl ester (43)

To (5-bromo-6-fluoro-pyridin-2-yl)-(4-methoxy-benzyl)-amine (42, 85 g,273 mmol) in 1.5 L of methanol in a 2 L Parr flask, triethylamine (77mL, 546 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.80 g, 7.10 mmol) are added. The reaction isheated at 100° C. under 100 psi of carbon monoxide overnight. Thereaction is cooled and filtered through celite and the filtrate isconcentrated under vacuum. The resulting material is dissolved indichloromethane and passed through a plug of silica gel, eluting withethyl acetate. The solvent is removed under vacuum to provide thedesired compound as a peach colored solid (43, 70 g, 241 mmol, 88%yield).

Step 4—Preparation of[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-3-yl]-methanol (44)

To 2-fluoro-6-(4-methoxy-benzylamino)-nicotinic acid methyl ester (43,70 g, 241 mmol) in 350 mL of tetrahydrofuran, lithium aluminum hydride(362 mL, 1 M in tetrahydrofuran, 362 mmol) is added dropwise whilecooling. The reaction is stirred at room temperature for 2 hours, thenquenched with dropwise addition of 14 mL of water, 14 mL of 15% aqueoussodium hydroxide, and 42 mL of water, sequentially. Then 500 mL ofmethyl tert-butyl ether is added and solids are removed by filtration.The filtrate is concentrated under vacuum and the resulting solid isdissolved in dichloromethane, passed through a plug of silica gel andeluted with 50-100% ethyl acetate in heptane. The solvent is removedunder vacuum to provide the desired compound as an off-white solid (44,63 g, 240 mmol, 100% yield).

Step 5—Preparation of2-fluoro-6-(4-methoxy-benzylamino)-pyridine-3-carbaldehyde (45)

To [2-fluoro-6-(4-methoxy-benzylamino)-pyridin-3-yl]-methanol (44, 63 g,240 mmol) in 1.25 L of ethyl acetate, manganese(IV) oxide (210 g, 2.416mol) is added. The reaction is stirred overnight at room temperature,then filtered through celite and the celite rinsed with ethyl acetate.The combined filtrates are concentrated under vacuum and the resultingsolid is triturated with heptane and collected by filtration to providethe desired compound as a white solid (45, 62 g, 238 mmol, 99% yield).

Step 6—Preparation of(6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acidtert-butyl ester (47)

2-Fluoro-6-(4-methoxy-benzylamino)-pyridine-3-carbaldehyde (45, 62 g,238 mmol), 600 mL of tert-butyl alcohol, di-tert-butyldicarbonate (46,83 mL, 357 mmol) and dimethylaminopyridine (2.91 g, 23.82 mmol) arecombined in a round bottom flask. The reaction is stirred at 30° C.overnight and then concentrated under vacuum. The resulting material ispurified by silica gel column chromatography, eluting with 0-20% ethylacetate in hexane. Appropriate fractions are combined and the solventsremoved under vacuum to provide the desired compound (47, 54 g, 150mmol, 62.9% yield).

Step 7—Preparation of{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamicacid tert-butyl ester (48)

To 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8,40 g, 97.0 mmol) in 400 mL of tetrahydrofuran under an atmosphere ofnitrogen at −20° C., isopropylmagnesium chloride (54.8 mL, 2 M intetrahydrofuran, 110 mmol) is added and the reaction allowed to warm to0° C. over 30 minutes. The reaction is cooled to −40° C. and(6-fluoro-5-formyl-pyridin-2-yl)-(4-methoxy-benzyl)-carbamic acidtert-butyl ester (47, 15.81 g, 43.9 mmol) in tetrahydrofuran is added.The reaction is allowed to warm to 0° C. over an hour, then quenchedwith brine and extracted with ethyl acetate. The organic layer is driedover sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is purified by silica gel columnchromatography, eluting with 0-40% ethyl acetate in hexane. Appropriatefractions are combined and the solvents removed under vacuum to providethe desired compound (48, 21 g, 32.4 mmol, 73.8% yield).

Step 8—Preparation of6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(49)

To{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamicacid tert-butyl ester (48, 21 g, 32.4 mmol) in 500 mL of acetonitrile,triethylsilane (51.7 mL, 324 mmol) and trifluoroacetic acid (24.93 mL,324 mmol) are added. The reaction is stirred at 50° C. for severalhours, then concentrated under vacuum, and the residue is taken up in250 mL of dichloromethane and 250 mL of trifluoroacetic acid is added.The mixture is stirred at reflux for several hours, then concentratedunder vacuum. The residue is taken up in ethyl acetate and poured intoaqueous potassium carbonate. The organic layer is separated,concentrated under vacuum and purified by silica gel columnchromatography, eluting with 0-5% methanol in dichloromethane.Appropriate fractions are combined and the solvents removed under vacuumto provide the desired compound (49, 5.2 g, 20.29 mmol, 62.7% yield).

5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-ylamine50

is prepared following the protocol of Scheme 7, replacing3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 with5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 4 instep 7.

Example 8: Synthesis of Aldehyde Reagents

Aldehyde reagents that are used in making compounds are preparedaccording to the following protocols. In these reactions, theunprotected aldehyde isolated after step 5, or the subsequentlyBoc-protected aldehyde may be used in preparation of compounds.

(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 57 is prepared in six steps from 2,6-difluoro-pyridine39 as shown in Scheme 8.

Step 1—Preparation of 2, 6-difluoro-nicotinic acid (51)

In a round bottom flask, to 2,6-difluoro-pyridine (39, 7.10 g, 61.7mmol) in 150.0 mL of tetrahydrofuran under an atmosphere of nitrogen at−78° C., n-butyllithium (26.0 mL, 2.50 M in hexane, 65.0 mmol) is slowlyadded. After 30 minutes, 3.0 g of dry ice is added and an hour later thereaction is allowed to warm to room temperature. The reaction is pouredinto water, extracted with ethyl acetate and the aqueous layer isadjusted to pH 4-5 with 1 N hydrochloric acid. This is extracted withethyl acetate and the organic layer is dried over sodium sulfate,filtered and the filtrate concentrated under vacuum to provide thedesired compound (51, 5.6 g).

Step 2—Preparation of 2,6-difluoro-nicotinic acid methyl ester (52)

In a round bottom flask, 2,6-difluoro-nicotinic acid (51, 5.60 g, 35.2mmol), 60.0 mL of methanol and sulfuric acid (1.0 mL, 19.0 mmol) arecombined and heated to reflux overnight. The reaction is poured intowater, adjusted to pH around 9 with 1M aqueous potassium carbonate, andextracted with ethyl acetate. The organic layer is dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum to providethe desired compound as a yellow oil (52, 3.5 g).

Step 3—Preparation of 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinicacid methyl ester (54)

To a round bottom flask, 2,6-difluoro-nicotinic acid methyl ester (52,2.00 g, 11.6 mmol) is combined with 20.0 mL of N,N-dimethylformamideunder an atmosphere of nitrogen at −40° C. To this,5-amino-2-methoxypyridine (53, 1.55 g, 12.5 mmol) and triethylamine (5.0mL, 36.0 mmol) are added and the reaction stirred at −40° C., thenwarmed to room temperature and reacted overnight. The reaction is thenheated to 50° C. over the weekend, then at 70° C. for 3 hours. Thereaction is poured into water and extracted with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (54, 1.20 g).

Step 4—Preparation of[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanol (55)

To 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinic acid methyl ester(54, 1.20 g, 4.33 mmol) in 50.0 mL of tetrahydrofuran, lithiumtetrahydroaluminate (8.66 mL, 1.00 M in tetrahydrofuran, 8.66 mmol) isadded and the reaction is stirred at room temperature for 3 hours.Sodium sulfate decahydrate (5 g) is added and after 1 hour, the reactionis filtered and the filtrate concentrated under vacuum. The resultingmaterial is purified by silica gel column chromatography eluting with20-100% ethyl acetate in hexane. Appropriate fractions are combined andconcentrated under vacuum to provide the desired compound (55, 700 mg).MS (ESI) [M+H⁺]⁺=250.1.

Step 5—Preparation of2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde (56)

To [2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanol (55,0.700 g, 2.81 mmol) in 20.0 mL of tetrahydrofuran, Dess-Martinperiodinane (1.44 g, 3.40 mmol) is added and the reaction stirred atroom temperature for 30 minutes. The reaction is poured into aqueouspotassium carbonate and extracted with ethyl acetate. The organic layeris dried over sodium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material is purified by silica gel columnchromatography eluting with 20-100% ethyl acetate in hexane. Appropriatefractions are combined and concentrated under vacuum to provide thedesired compound (56, 450 mg). MS (ESI) [M+H⁺]⁺=248.0.

Step 6—Preparation of(6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic acidtert-butyl ester (57)

To 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde (56,2.21 g, 8.94 mmol) in 50 mL of tetrahydrofuran, di-tert-butyldicarbonate(46, 2.82 g, 12.9 mmol) and 4-dimethylaminopyridine (0.30 g, 2.4 mmol)are added and the reaction stirred at room temperature overnight. Thereaction is concentrated under vacuum and the resulting material ispurified by silica gel column chromatography eluting with 20-100% ethylacetate in hexane. Appropriate fractions are combined and concentratedunder vacuum to provide the desired compound (57, 1.39 g).

Additional aldehydes are prepared similarly to the protocol of scheme 8,as shown in the following table, replacing 5-amino-2-methoxypyridine 53with a suitable amine compound in step 3. While the table indicates theBoc-protected aldehyde, the non-Boc protected aldehyde may be isolatedafter step 5.

TABLE 3 Step 3 amine compound Final aldehyde

Example 9: Synthesis of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amineP-3001

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amineP-3001 is prepared in one step from1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine37 and cyclohexanamine 62 as shown in Scheme 9.

Step 1—Preparation of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amine(83001)

In a microwave vial, to1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(37, 60 mg, 0.13 mmol) in 1.0 mL of N-methylpyrrolidinone,cyclohexanamine (62, 0.20 g, 2.0 mmol) is added. The reaction is heatedat 155° C. for 25 minutes in a microwave, then potassium hydroxide (1.0mL, 1.00 M in water, 1.0 mmol) is added and the reaction heated at 95°C. for 15 minutes in a microwave. The reaction is poured into water andextracted with ethyl acetate. The organic layer is dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fractions arecollected and concentrated under vacuum to provide the desired compound(P-3001, 11.4 mg). MS (ESI) [M+H⁺]⁺=341.9.

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amineP-3009 was prepared similarly to Scheme 9, replacing step 1 with thefollowing steps 1a and 2:

Step 1a—Preparation of[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine(64)

In a microwave vial, to1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(37, 0.140 g, 0.302 mmol) in 2.0 mL of N-methylpyrrolidinone,4-methylcyclohexylamine (63, 0.30 g, 2.6 mmol) is added. The reaction isheated at 160° C. for 20 minutes in a microwave, then poured into waterand extracted with ethyl acetate. The organic layer is dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fractions arecombined and concentrated under vacuum to provide the desired compound(64, 0.120 g). MS (ESI) [M+H⁺]⁺=496.4.

Step 2—Preparation of[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine(P-3009)

To[5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-cyclohexyl)-amine(64, 0.120 g, 0.242 mmol) in 5.0 mL of tetrahydrofuran,tetrabutylammonium fluoride trihydrate (0.20 g, 0.63 mmol) is added. Thereaction is stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer is dried oversodium sulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fractions arecollected and concentrated under vacuum to provide the desired compound(P-3009, 1.4 mg). MS (ESI) [M+H⁺]⁺=355.95.

Additional compounds are prepared following the protocol of Scheme 9.Compounds are made substituting cyclohexanamine 62 with a suitable amineand optionally substituting1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine37 with1-benzenesulfonyl-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine38. The following compounds are made using this procedure:

-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopentyl-amine    (P-3003),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4,4-difluoro-cyclohexyl)-amine    (P-3004),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclopropyl-amine    (P-3005),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cycloheptyl-amine    (P-3006),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclobutyl-amine    (P-3007),-   (4-Fluoro-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3010),-   (4-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3011),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine    (P-3012),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-phenyl)-amine    (P-3014),-   (2-Chloro-phenyl)-[5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3015),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-phenyl)-amine    (P-3016),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-phenyl)-amine    (P-3017),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine    (P-3018),-   (6-Methoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3020),-   (4-Methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3021),-   (4-Fluoro-3-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3022),-   (3-Fluoro-4-methoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3023),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-propoxy-phenyl)-amine    (P-3024),-   (4-Ethyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3025),-   (4-Ethoxy-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3026),-   (6-Ethoxy-pyridin-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3027),-   [5-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3028),-   (5-tert-Butyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3029),-   (4-tert-Butyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    amine (P-3030),-   1,1,1,3,3,3-Hexafluoro-2-{4-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylamino]-phenyl}-propan-2-ol    (P-3031),-   (5-Cyclopropyl-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3032),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine    (P-3033),-   (1-Ethyl-1H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3035),-   (1-Ethyl-1H-pyrazol-4-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3036),-   [5-(5-Methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-trifluoromethyl-2H-pyrazol-3-yl)-amine    (P-3037), and-   (5-Isopropoxy-2H-pyrazol-3-yl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine    (P-3038).

The following table indicates the2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine(column 2) and amine compound (column 3) used in step 1 to afford thedesired compound (column 4). The compound number is provided in column1, and the observed mass is in column 5.

TABLE 4 Comp. Amine MS (ESI) number pyrrolo[2,3-b]pyridine structureCompound structure [M + H⁺]⁺ P-3003

328.0 P-3004

377.9 P-3005

300.0 P-3006

356.3 P-3007

314.2 P-3010

334.1 P-3011

370.8 P-3012

354.0 P-3014

353.9 P-3015

369.9 P-3016

365.9 P-3017

353.9 P-3018

384.9 P-3020

347.1 P-3021

346.2 P-3022

363.9 P-3023

363.9 P-3024

374.0 P-3025

344.0 P-3026

360.0 P-3027

501.3 P-3028

399.9 P-3029

362.0 P-3030

372.0 P-3031

482.3 P-3032

346.0 P-3033

362.1 P-3035

334.2 P-3036

333.9 P-3037

374.0 P-3038

363.9

(4-Methanesulfonyl-phenyl)-[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amineP-3034

is prepared by oxidizing the product of Scheme 9 step 1a in thepreparation of[5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine(P-3033), prior to reaction of step 2, according to the following step1b:

Step 1b—Preparation of[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methanesulfonyl-phenyl)-amine(66)

To[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methylsulfanyl-phenyl)-amine(65, 80 mg, 0.16 mmol) in 10.0 mL of dichloromethane,meta-chlorperoxybenzoic acid (78.6 mg, 0.351 mmol) is added at 0° C. Thereaction is stirred at room temperature for 30 minutes, thenconcentrated under vacuum to provide[5-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methanesulfonyl-phenyl)-amine66, which is reacted according to Scheme 9 step 2 to provide the desiredcompound (P-3034, 30.7 mg). MS (ESI) [M+H⁺]⁺=393.9.

Example 10: Synthesis ofcyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3008

Cyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3008 is prepared in one step from6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine49 and cyclohexanone 67 as shown in Scheme 10.

Step 1—Preparation ofcyclohexyl-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(83008)

To6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine(49, 100 mg, 0.39 mmol) and cyclohexanone (67, 0.0465 mL, 0.449 mmol) in3.00 mL of acetonitrile, triethylsilane (0.400 mL, 2.50 mmol) andtrifluoroacetic acid (0.300 mL, 3.89 mmol) were added. The reaction wasstirred at 80° C. overnight, then extracting with ethyl acetate and 1Naqueous sodium bicarbonate. The organic layer was washed with brine,dried with magnesium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material was purified by silica gel columnchromatography, eluting with 0-60% ethyl acetate in hexane. Appropriatefractions were combined and concentrated under vacuum to provide thedesired compound (P-3008, 115 mg). MS (ESI) [M+H⁺]⁺=339.0.

[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(4,4-difluoro-cyclohexyl)-amineP-3013

is prepared following the protocol of Scheme 10, replacing6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine49 with5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-ylamine50 and replacing cyclohexanone 67 with 4,4-difluoro-cyclohexanone. MS(ESI) [M+H⁺]⁺=394.9 and 396.9.

Example 11: Synthesis of[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-3019

[6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-3019 is prepared in two steps from3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 and2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde 56 asshown in Scheme 11.

Step 6—Preparation of[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(68)

To a solution of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1.02g, 2.461 mmol) in 6.0 mL of tetrahydrofuran at −50° C. under nitrogen,isopropylmagnesium chloride (1.23 mL, 2.00 M in tetrahydrofuran, 2.46mmol) is added slowly. The reaction is allowed to warm to 5° C. over 70minutes, then cooled to −45° C., followed by addition of2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridine-3-carbaldehyde (56,0.165 g, 0.667 mmol) in 2.0 mL of tetrahydrofuran. The reaction isallowed to warm to room temperature over an hour, then poured into waterand extracted with ethyl acetate. The organic layer is dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatographyeluting with 20-100% ethyl acetate in hexane. Appropriate fractions arecombined and concentrated under vacuum to provide the desired compound(68, 330 mg). MS (ESI) [M+H⁺]⁺=536.2.

Step 7—Preparation of[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine(83019)

To[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol(68, 0.220 g, 0.411 mmol) in 20.0 mL of 1,2-dichloroethane,triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL, 13mmol) are added and the reaction stirred at 80° C. for 3 hours. Thereaction is poured into water and extracted with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (P-3019, 105.1 mg). MS (ESI) [M+H⁺]⁺=364.2.

[6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-4001 and[6-Fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-4002

are prepared similarly to the protocol of Scheme 11, replacing3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 with5-iodo-4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine 14and 5-iodo-4-methyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine16, respectively in step 1.

Example 12: Synthesis of(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3039 or[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-3045

(6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3039 or[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-3045 are prepared in two steps or three steps from3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8, and(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 69 as shown in Scheme 12.

Step 1—Preparation of(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamicacid tert-butyl ester (70)

To a solution of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 0.43g, 1.0 mmol) in 5 mL of tetrahydrofuran at −40° C. under nitrogen,isopropylmagnesium chloride (0.51 mL, 2.00 M in tetrahydrofuran, 1.0mmol) is added slowly. The reaction is allowed to warm to −5° C. over 60minutes, then cooled to −45° C., followed by addition of(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (69, 0.06 g, 0.2 mmol) in 2.0 mL of tetrahydrofuran.The reaction is allowed to warm to room temperature over 2 hours, thenpoured into water and extracted with ethyl acetate. The organic layer isdried over sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is purified by silica gel columnchromatography eluting with 20-100% ethyl acetate in hexane. Appropriatefractions are combined and concentrated under vacuum to provide thedesired compound (70, 108.1 mg).

Step 2—Preparation of(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine(P-3039)

To(6-ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamicacid tert-butyl ester (70, 108.1 mg, 0.166 mmol) in 4.54 mL of1,2-dichloroethane, triethylsilane (0.454 mL, 2.84 mmol) andtrifluoroacetic acid (0.27 mL, 3.5 mmol) are added and the reactionstirred at 80° C. for 4 hours. The reaction is poured into aqueouspotassium carbonate and extracted with ethyl acetate. The organic layeris dried over sodium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material is purified by silica gel columnchromatography eluting with 25-100% ethyl acetate in hexane. Appropriatefractions are combined and concentrated under vacuum to provide thedesired compound (P-3039), which is further purified by additionalchromatography.

Step 2a—Preparation of(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (71)

(6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamicacid tert-butyl ester (70, 0.400 g, 0.616 mmol) is alternativelydissolved in 11.8 mL of dichloromethane, and Dess-Martin periodinane(0.100 g, 0.236 mmol) is added. The reaction is stirred at roomtemperature for 30 minutes, then concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fraction arecombined and concentrated under vacuum to provide the desired compound(71, 0.200 g).

Step 3a—Preparation of[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-3045)

To(6-ethoxy-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (71, 0.200 g, 0.309 mmol) in 10 mL of1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.0 mmol) is added.The reaction is stirred at 80° C. for 2 hours, then poured into aqueouspotassium carbonate and extracted with ethyl acetate. The organic layeris dried over sodium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material is purified by silica gel columnchromatography, eluting with 2-15% methanol in dichloromethane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (P-3045, 60.7 mg). MS (ESI) [M+H⁺]⁺=391.9.

Additional compounds are prepared following the protocol of Scheme 12.Compounds are made substituting either of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 with asuitable TIPS-protected 1H-pyrrolo[2,3-b]pyridine or7H-pyrrolo[2,3-d]pyrimidine and(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 69 with a suitable Boc-protected aldehyde in step 1.The following compounds are made using this procedure:

-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-3019),-   [2-Fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3040),-   [6-Fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3041),-   [5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-3042),-   [2-Fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3043),-   (5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-3044),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine    (P-3048),-   [6-(6-Ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone    (P-3049),-   (6-Chloro-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4003),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4005),-   (6-Ethoxy-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4006),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4007),-   (6-Ethyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4009),-   [6-Fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4010),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4011),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4012),-   (1-Ethyl-1H-pyrazol-4-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine    (P-4013),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4017),-   [5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine    (P-4018),-   (6-Bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine    (P-4020),

The following table indicates the TIPS-protected1H-pyrrolo[2,3-b]pyridine (column 2) and Boc-protected aldehyde compound(column 3) used in step 1 to afford the desired compound (column 4). Thecompound number is provided in column 1, and the observed mass is incolumn 5.

TABLE 5 pyrrolo[2,3- b]pyridine or Comp. pyrrolo[2,3- MS (ESI) numberd]pyrimidine Aldehyde Compound structure [M + H⁺]⁺ P-3019

363.9 P-3040

378.0 P-3041

347.8 P-3043

361.9 P-3042

367.9 P-3044

382.0 P-3048

362.0 P-3049

376.1 P-4003

385.0 P-4005

394.95 P-4024

409.2 P-4006

378.95 P-4007

379.0 P-4009

P-4010

365.0 P-4011

367.9 P-4012

382.1 P-4013

351.9 P-4017

379.0 P-4018

394.8 P-4025

409.2 P-4020

442.9 444.9

(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amineP-4004

is prepared from the intermediate isolated after step 1 in thepreparation of P-4003 according to the following steps 1b and 2b.

Step 1b—Preparation of[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol(73)

To(6-chloro-pyridin-3-yl)-{6-fluoro-5-[hydroxy-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-pyridin-2-yl}-carbamicacid tert-butyl ester (72, 105 mg, 0.160 mmol) in 3.8 mL of toluene,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) 1:1 complexwith dichloromethane (13.0 mg, 0.016 mmol) is added under an atmosphereof nitrogen. The reaction is stirred for 5 minutes, thencyclopropylmagnesium bromide (17, 1.60 mL, 1.0 M in tetrahydrofuran,1.60 mmol) is added slowly. The reaction is heated at 65° C. for 5hours, then poured into water and extracted with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography, eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (73, 70 mg). MS (ESI) [M+H⁺]⁺=563.6.

Step 2b—Preparation of(6-cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine(P-4004)

To[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methoxy-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol(73, 70 mg, 0.12 mmol) in 10.0 mL of 1,2-dichloroethane, triethylsilane(1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.60 mL, 7.8 mmol) areadded and the reaction stirred at 80° C. for 4 hours. The reaction ispoured into aqueous potassium carbonate and extracted with ethylacetate. The organic layer is dried over sodium sulfate, filtered andthe filtrate concentrated under vacuum. The resulting material ispurified by silica gel column chromatography, eluting with 20-100% ethylacetate in hexane. Appropriate fractions are combined and concentratedunder vacuum to provide the desired compound (P-4004, 11.8 mg). MS (ESI)[M+H⁺]⁺=390.9.

(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3050

is prepared similarly to the protocol of Scheme 12, step 1, followed bysteps 1b and 2b, where(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 69 is replaced with(6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester in step 1. MS (ESI) [M+H⁺]⁺=374.2.

[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-3051

is similarly prepared from the intermediate formed from step 1b in thepreparation of P-3050, reacting similarly to step 2a of Scheme 12, andthen according to the following step 3b.

Step 3b—Preparation of[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(P-3051)

To[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone(74, 134 mg, 0.25 mmol) in 10 mL of tetrahydrofuran, tetrabutylammoniumfluoride, trihydrate (85.53 mg, 0.27 mmol) is added and the reactionstirred at room temperature for 30 minutes. Water is added and themixture is extracted with ethyl acetate. The organic layer is washedwith water and brine, dried with magnesium sulfate, filtered and thefiltrate concentrated under vacuum. The resulting material is purifiedby silica gel column chromatography, eluting with ethyl acetate inhexane. Appropriate fractions are combined and concentrated under vacuumto provide the desired compound (P-3051, 82 mg). MS (ESI) [M+H⁺]⁺=388.0.

[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanoneP-3052 and(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amineP-3053

were prepared similarly to the protocols used for P-3051 and P-3052,respectively, where3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (preparedsimilarly to the protocol of Scheme 1, replacing5-chloro-1H-pyrrolo[2,3-b]pyridine 1 with 1H-pyrrolo[2,3-b]pyridine instep 1) was used in place of3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 8 instep 1. P-3052 MS (ESI) [M+H⁺]⁺=374.0. P-3053 MS (ESI) [M+H⁺]⁺=359.9.

[5-(4-Ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-pyridin-3-yl-amineP-4021

is prepared from(6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amineP-4020 according to the following step 3c.

Step 3b—Preparation of[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-pyridin-3-yl-amine(P-4021)

To(6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine(P-4020, 0.040 g, 0.090 mmol) in 5.0 mL of tetrahydrofuran undernitrogen at −78° C., tert-butyllithium (0.531 mL, 1.70 M in hexane,0.903 mmol) is added. The reaction is stirred at −78° C. for 30 minutes,then poured into water and extracted with ethyl acetate. The organiclayer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified withsilica gel column chromatography, eluting with 20-100% ethyl acetate inhexane. Appropriate fractions are combined and concentrated under vacuumto provide the desired compound (P-4021, 25.7 mg). MS (ESI)[M+H⁺]⁺=364.9.

Example 13: Synthesis of[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-4023 or(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanoneP-4022

[5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amineP-4023 or4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanoneP-4022 are prepared in three steps or four steps from7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 32and (6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester 57 as shown in Scheme 13.

Step 1—Preparation of{5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester (75)

To a solution of7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (32,0.760 g, 1.79 mmol) in 5.43 mL of tetrahydrofuran at −40° C. undernitrogen, isopropylmagnesium chloride (0.892 mL, 2.0 M intetrahydrofuran, 1.78 mmol) is added slowly. The reaction is allowed towarm to −5° C. over 75 minutes, then cooled to −45° C. and(6-fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-yl)-carbamic acidtert-butyl ester (57, 0.38 g, 1.1 mmol) in 2.0 mL of tetrahydrofuran isadded. The reaction is allowed to warm to room temperature over 2 hours,then poured into water and extracted with ethyl acetate. The organiclayer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum. The resulting material is purified by silicagel column chromatography, eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (75, 0.64 g). MS (ESI) [M+H⁺]⁺=647.2.

Step 2—Preparation of[5-(7-Benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine(76)

To{5-[(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester (75, 0.290 g, 0.448 mmol) in 9.93 mL of1,2-dichloroethane, triethylsilane (0.31 mL, 2.0 mmol) andtrifluoroacetic acid (0.16 mL, 2.0 mmol) are added and the reactionstirred at 80° C. for 4 hours. The reaction is poured into aqueouspotassium carbonate and extracted with ethyl acetate. The organic layeris dried with sodium sulfate, filtered and the filtrate concentratedunder vacuum to provide the desired compound (76, 170 mg). MS (ESI)[M+H⁺]⁺=530.9.

Step 3—Preparation of[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine(P-4023)

To[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-amine(76, 0.170 g, 0.320 mmol) in 10.0 mL of tetrahydrofuran,tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is addedand the reaction is stirred at room temperature overnight. The reactionis poured into water and extracted with ethyl acetate. The organic layeris dried with sodium sulfate, filtered and the filtrate concentratedunder vacuum. The resulting material is purified by silica gel columnchromatography, eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (P-4023, 100.4 mg). MS (ESI) [M+H⁺]⁺=390.8.

Step 2a—Preparation of[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester (77)

{5-[(7-Benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester (75, 0.350 g, 0.541 mmol) is alternativelydissolved in 10.0 mL of dichloromethane, and Dess-Martin periodinane(0.211 g, 0.498 mmol) is added. The reaction is stirred at roomtemperature for 30 minutes, then concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 10-100% ethyl acetate in hexane. Appropriate fraction arecombined and concentrated under vacuum to provide the desired compound(77, 340 mg). MS (ESI) [M+H⁺]⁺=645.4.

Step 3a—Preparation of(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone(78)

To[5-(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3-yl)-carbamicacid tert-butyl ester (77, 0.340 g, 0.527 mmol) in 10 mL of1,2-dichloroethane, trifluoroacetic acid (0.80 mL, 10.4 mmol) is added.The reaction is stirred at 80° C. for 45 minutes, then poured intoaqueous potassium carbonate and extracted with ethyl acetate. Theorganic layer is dried over sodium sulfate, filtered and the filtrateconcentrated under vacuum to provide the desired compound (78, 235 mg).MS (ESI) [M+H⁺]⁺=545.4.

Step 4a—Preparation of(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone(P-4022)

To(7-benzenesulfonyl-4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-pyridin-3-yl]-methanone(78, 0.235 g, 0.432 mmol) in 10.0 mL of tetrahydrofuran,tetrabutylammonium fluoride, trihydrate (0.174 g, 0.551 mmol) is added.The reaction is stirred at room temperature overnight, then poured intowater and extracted with ethyl acetate. The organic layer is dried oversodium sulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane. Appropriate fraction arecombined and concentrated under vacuum to provide the desired compound(P-4022, 104.5 mg). MS (ESI) [M+H⁺]⁺=405.0.

Additional compounds are prepared following the protocol of Scheme 13.4-Cyclopropyl-5-iodo-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine33 may be used in place of7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 32.Compounds are made substituting either of7-benzenesulfonyl-4-cyclopropyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 32with a suitable benzenesulfonyl or 4-methylbenzenesulfonyl-protected7H-pyrrolo[2,3-d]pyrimidine or 1H-pyrrolo[2,3-b]pyridine and(6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester 57 with a suitable Boc-protected aldehyde in step 1. Insome instances, a non-Boc protected aldehyde is used as indicated in thefollowing table (with no step 3a in this case). The following compoundsare made using this procedure:

-   (6-Ethoxy-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4008),-   (1-Ethyl-1H-pyrazol-4-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4014),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methyl-pyridin-3-yl)-amine    (P-4015),-   (6-Ethyl-pyridin-3-yl)-{6-fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-amine    (P-4016),-   {6-Fluoro-5-[4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-yl)-amine    (P-4019),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethoxy-pyridin-3-yl)-amine    (P-4026),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4027),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-ethyl-pyridin-3-yl)-amine    (P-4028),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(6-ethyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4029),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methyl-pyridin-3-yl)-amine    (P-4030),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(6-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4031),-   [6-(6-Ethoxy-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone    (P-4032),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(1-ethyl-1H-pyrazol-4-yl)-amine    (P-4036),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[6-(1-ethyl-1H-pyrazol-4-ylamino)-2-fluoro-pyridin-3-yl]-methanone    (P-4037),-   [5-(4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-methyl-pyridin-3-yl)-amine    (P-4038),-   (4-Cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-[2-fluoro-6-(5-methyl-pyridin-3-ylamino)-pyridin-3-yl]-methanone    (P-4039),

The following table indicates the Benzenesulfonyl-protected1H-pyrrolo[2,3-b]pyridine (column 2) and Boc-protected aldehyde compound(column 3) used in step 1 to afford the desired compound (column 4). Thecompound number is provided in column 1, and the observed mass is incolumn 5.

TABLE 6 Comp. pyrrolo[2,3- MS (ESI) number b]pyridine Aldehyde Compoundstructure [M + H⁺]⁺ P-4008

439.0 P-4014

412.0 P-4015

409.0 P-4016

423.0 P-4019

424.9 P-4026

404.9 P-4027

418.8 P-4028

389.0 P-4029

402.9 P-4030

375.0 P-4031

388.9 P-4032

393.1 P-4036

378.0 P-4037

392.0 P-4038

375.1 P-4039

389.1 P-4042

P-4043

Example 14: Synthesis of[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanoneP-4040 and(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amineP-4041

[6-(6-Cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanoneP-4040 and(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amineP-4041 are prepared in three steps from4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine19 and (6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamicacid tert-butyl ester 80 as shown in Scheme 14.

Step 1—Preparation of(6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamicacid tert-butyl ester (81)

To4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine(19, 0.72 g, 1.64 mmol) in 6.0 mL of tetrahydrofuran at −40° C. undernitrogen, isopropylmagnesium chloride (0.82 mL, 2.01 M intetrahydrofuran, 1.65 mmol) is added slowly. The reaction is allowed towarm to −5° C. in 75 minutes, then cooled to −45° C. and(6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acidtert-butyl ester (80, 0.48 g, 1.38 mmol) in 5.0 mL is added. Thereaction is allowed to warm to room temperature in 2 hours, then pouredinto water and extracted with ethyl acetate. The organic layer is driedover sodium sulfate, filtered and the filtrate concentrated undervacuum. The resulting material is purified by silica gel columnchromatography, eluting with 20-100% ethyl acetate in hexane.Appropriate fractions are combined and concentrated under vacuum toprovide the desired compound (81, 0.51 g). MS (ESI) [M+H⁺]⁺=667.2).

Step 2—Preparation of[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol(82)

To(6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamicacid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of toluene,[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g,0.17 mmol) is added under nitrogen and the reaction stirred for 5minutes. Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M intetrahydrofuran, 7.65 mmol) is added slowly and the reaction is heatedat 65° C. for 2 hours. The reaction is poured into water and extractedwith ethyl acetate. The organic layer is dried over sodium sulfate,filtered and the filtrate concentrated under vacuum. The resultingmaterial is purified by silica gel column chromatography, eluting with20-100% ethyl acetate in hexane. Appropriate fractions are combined andconcentrated under vacuum to provide the desired compound (82, 400 mg).

Step 3—Preparation of[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone(P-4040) and(6-cyclopropyl-pyridin-3-yl)-[5-(4-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine(P-4041)

To[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol(82, 400 mg, 0.7 mmol) in 30 mL of dichloromethane, triethylsilane (2.6mL, 16.28 mmol) and trifluoroacetic acid (1.5 mL, 15.13 mmol) are added,and the reaction is stirred at 80° C. for 3 hours. The reaction ispoured into aqueous potassium carbonate and extracted with ethylacetate. The organic layer is washed with brine, dried over sodiumsulfate, filtered and the filtrate concentrated under vacuum. Theresulting material is purified by silica gel column chromatography,eluting with 20-100% ethyl acetate in hexane to give a mixture ofcompounds P-4040 and P-4041. These are separated by preparative HPLC toprovide the isolated compounds (P-4040, 3.0 mg, MS (ESI) [M+H⁺]⁺=414.9),(P-4041, 37.9 mg, MS (ESI) [M+H⁺]⁺=401.0).

(6-Cyclopropyl-pyridin-3-yl)-[6-fluoro-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amineP-4044 and[6-(6-cyclopropyl-pyridin-3-ylamino)-2-fluoro-pyridin-3-yl]-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanoneP-4045

are prepared similarly to Scheme 14, where4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine19, is replaced in step 1 with5-iodo-4-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared similarly toScheme 4 steps 1 and 2). P-4044, 2.5 mg, MS (ESI) [M+H⁺]⁺ 375.0. P-4045,5.3 mg, MS (ESI) [M+H⁺]⁺=388.9.

Example 15: Synthesis of[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone(P-4115)

Step 1—Preparation of tert-butylN-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate85

To a solution of7-(benzenesulfonyl)-4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidine (1, 0.43 g,1.01 mmol) in Tetrahydrofuran (5 mL) at −30° C. under nitrogen was added2.0 M Isopropylmagnesium Chloride in Tetrahydrofuran (0.5 ml) slowly.The reaction was allowed to warm to −5° C. in 75 minutes. Then, thereaction was cooled to −45° C., followed by adding tert-butylN-(6-fluoro-5-formyl-2-pyridyl)-N-(6-methyl-3-pyridyl)carbamate (84,0.24 g, 0.72 mmol) in THF (3.0 mL). The reaction was allowed to warm toroom temperature in around 2 hours. The reaction was poured in to water,extracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, and filtered. The filtrate was concentrated, purifiedwith silica gel column chromatography eluting with 20%-100% ethylacetate in hexane to give product (85, 0.41 g, 90.6%). MS (ESI)[M+H+]+=625.0.

Step 2—Preparation of tert-butylN-[5-[[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate86

To tert-butylN-[5-[[7-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate(85, 75 mg, 0.12 mmol) in Isopropyl alcohol (0.80 mL) was added 2Mmethylamine in THF (0.6 ml). The resulting solution was stirred at 40°C. for 6 hours. The reaction was concentrated to give product (86, 70mg, 94.2%). MS (ESI) [M+H+]+=620.

Step 3—Preparation of tert-butylN-[5-[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate87

To tert-butylN-[5-[[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-hydroxy-methyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate(86, 0.07 g, 0.11 mmol) in DCM (10 mL) was added DMP (0.06 g, 0.14mmol). The reaction was stirred at room temperature for 20 minutes. Thereaction was concentrated, and purified with silica gel columnchromatography eluting with 20% to 100% ethyl acetate in hexane to giveproduct (87, 0.065 g, 93.6%).

Step 4—Preparation of[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone;2,2,2-trifluoroacetic acid 88

To tert-butylN-[5-[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-6-fluoro-2-pyridyl]-N-(6-methyl-3-pyridyl)carbamate(87, 65 mg, 0.11 mmol) in dichloroethane (10 mL) was added TFA (0.65 ml,8.75 mmol). The reaction was heated 80° C. for 1 hour. The reaction wasconcentrated to give crude product (CF₃COOH salt) around (88, 0.080 g,86.4%). MS (ESI) [M+H+]+=518. MS is the free base product.

Step 5—Preparation of[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]-(4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanoneP-4115

To[7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone;2,2,2-trifluoroacetic acid (88, 80 mg, 0.09 mmol) in Methanol (6 ml) wasadded KOH (0.1 g, 1.78 mmol). The reaction was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated andpurified with silica gel column chromatography eluting with 2% to 25%methanol in methylene chloride to give product (P-4115, 9.6 mg, 27.3%).MS (ESI) [M+H+]+=377.9.

Table 2 below provides compounds prepared according to the syntheticprotocols set forth in Schemes 14 and 15. The structures werecharacterized by mass spectroscopy and ¹H and ¹³C NMR spectroscopies.

TABLE 2 MS (ESI) No. Compound Structure [M + H⁺]⁺ P-4046

407.2 P-4047

461.3 P-4048

390.1 P-4049

462.1 P-4050

435.0 P-4051

419.0 P-4052

472.95 P-4053

431.0 P-4054

405.0 P-4055

436.5 P-4056

498.5 P-4057

489.0 P-4058

420.9 P-4059

447.1 P-4060

418.0 P-4061

473.0 P-4062

431.1 P-4063

405.0 P-4064

445.0 P-4065

377.9 P-4066

422.0 P-4067

434.5 P-4068

422.0 P-4069

449.5 P-4070

450.0 P-4071

539.5 P-4072

502.5 P-4073

464.0 P-4074

491.5 P-4075

448.0 P-4076

434.5 P-4077

450.0 P-4078

436.5 P-4079

452.0 P-4080

436.5 P-4081

408.5 P-4082

462.5 P-4083

394.5 P-4084

462.5 P-4085

406.0 P-4086

469.5 P-4087

455.2 P-4088

413.2 P-4089

387.2 P-4090

470.2 P-4091

458.0 P-4092

432.0 P-4093

429.9 P-4094

403.9 P-4095

432.5 P-4096

496.5 P-4097

500.5 P-4098

450.0 P-4099

446.5 P-4100

434.5 P-4101

397.5 P-4102

369.1 P-4103

462.1 P-4104

462.1 P-4105

422.0 P-4106

422.2 P-4107

420.2 P-4108

393.9 P-4109

412.9 P-4110

384.9 P-4111

446.1 P-4112

446.0 P-4113

418.1 P-4114

406.0 P-4115

377.9 P-4116

462.1 P-4117

420.0 P-4118

432.2 P-4119

436.1 P-4120

460.1 P-4121

434.1 P-4122

420.0 P-4123

406.5 P-4124

391.9 P-4125

418.0 P-4126

420.0 P-4127

417.0 P-4128

459.0 P-4129

417.0 P-4130

458.0 P-4131

379.0 P-4132

502.5 P-4133

500.5

The compounds set forth in Table 7 below are prepared according to thesynthetic protocols set forth in Schemes 14 and 15. The structures arecharacterized by mass spectroscopy and ¹H and ¹³C NMR spectroscopies.

TABLE 7 No Name Structure P-4134 [2-fluoro-6-[(4-fluorocyclohexyl)amino]-3-pyridyl]- [4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4135 [4-(ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]methanone

P-4136 [2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-[4-(isopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4137 [4-(cyclopropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3- pyridyl]methanone

P-4138 [2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-[4-(2,2,2-trifluoroethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4139 [4-[[(1R)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2- fluoro-6-[(4-fluorocyclohexyl)amino]-3- pyridyl]methanone

P-4140 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[2- fluoro-6-[(4-fluorocyclohexyl)amino]-3- pyridyl]methanone

P-4141 [2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-[4-(methoxymethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4142 [2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-[4-(3-methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4143 [2-fluoro-6-[(4- fluorocyclohexyl)amino]-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4144 [4-(cyclobutylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(4- fluorocyclohexyl)amino]-3- pyridyl]methanone

P-4145 [6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone

P-4146 [6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4147 [6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(propylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone

P-4148 [6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(isopropylamino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]methanone

P-4149 [6-[(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]-[4-(2,2,2- trifluoroethylamino)-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4150 [4-[[(1R)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone

P-4151 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(3,3-difluorocyclobutyl)amino]-2-fluoro-3-pyridyl]methanone

P-4152 [6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(methoxymethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4153 [6-[(3,3- 15difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4154 [4-(cyclobutylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(3,3-difluorocyclobutyl)amino]-2- fluoro-3-pyridyl]methanone

P-4155 [6-[(3,3-difluorocyclobutyl)amino]- 2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4156 [6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4157 [6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-(2-methoxyethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4158 [4-(cyclobutylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-2- fluoro-3-pyridyl]methanone

P-4159 [6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4160 [4-[[(1R)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone

P-4161 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]methanone

P-4162 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-(ethylamino)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4163 [4-(cyclobutylamino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl]-[6-[(4,4-difluorocyclohexyl)amino]-5- fluoro-3-pyridyl]methanone

P-4164 [6-[(4,4-difluorocyclohexyl)amino]- 5-fluoro-3-pyridyl]-[4-(methoxymethylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4165 [6-[(4,4-difluorocyclohexyl)amino]- 5-fluoro-3-pyridyl]-[4-(3-methoxypropylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4166 [6-[(4,4-difluorocyclohexyl)amino]- 5-fluoro-3-pyridyl]-[4-(tetrahydropyran-4-ylamino)-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4167 [4-[[(1R)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone

P-4168 [4-[[(1S)-1- cyclopropylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-[6- [(4,4-difluorocyclohexyl)amino]-5-fluoro-3-pyridyl]methanone

P-4169 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1-methylpropyl]amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4170 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy-1-methyl- propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4171 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1- (hydroxymethyl)propyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4172 4-[[5-[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]pyrrolidin- 2-one

P-4173 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-hydroxy-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4174 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3- hydroxycyclohexyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4175 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclopentyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4176 1-[3-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3- carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin- 1-yl]ethanone

P-4177 (2R)-2-[[5-[6-[(6-cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3- carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4- yl]amino]cyclohexanone

P-4178 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothiolan-3-yl)amino]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4179 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclohexyl]amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4180 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2-methoxy-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4181 4-[[5-[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]piperidin-2- one

P-4182 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2-trifluoro-1-methyl- ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4183 4-[[5-[6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl]amino]-1-methyl-piperidin-2-one

P-4184 [6-[(6-cyclopropyl-3- pyridyl)amino]-2-fluoro-3-pyridyl]-[4-[(1,1-dioxothian-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5-yl]methanone

P-4185 1-cyclopropyl-4-[[5-[6-[(6- cyclopropyl-3-pyridyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one

P-4186 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1S)-1- methylpropyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4187 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[(3-hydroxy- 1-methyl-propyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4188 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-1- (hydroxymethyl)propyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4189 4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one

P-4190 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2- hydroxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4191 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,3R)-3- hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4192 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclopentyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4193 1-[3-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-1-yl]ethanone

P-4194 (2R)-2-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexanone

P-4195 [6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-[(1,1-dioxothiolan-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4196 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R,2R)-2- hydroxycyclohexyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4197 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2- methoxy-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4198 4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]piperidin-2-one

P-4199 [6-[(4,4-difluorocyclohexyl)amino]-2-fluoro-3-pyridyl]-[4-[[(1R)-2,2,2- trifluoro-1-methyl-ethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4200 4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]-1-methyl-piperidin-2-one

P-4201 [6-[(4,4-difluorocyclohexyl)amino]- 2-fluoro-3-pyridyl]-[4-[(1,1-dioxothian-3-yl)amino]-7H- pyrrolo[2,3-d]pyrimidin-5- yl]methanone

P-4202 1-cyclopropyl-4-[[5-[6-[(4,4- difluorocyclohexyl)amino]-2-fluoro-pyridine-3-carbonyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino]pyrrolidin-2-one

Example 16: Compound Properties

While the inhibitory activity of the compounds on any of Fms, Kit,Flt-3, TrkA, TrkB and TrkC kinase is important to their activity intreating of disease, the compounds described herein show favorableproperties that provide advantages as a pharmaceutical as well. In someinstances, Fms selectivity relative to Kit and other kinases providespreferred activity for treating certain diseases, such as rheumatoidarthritis, Alzheimer's disease, Parkinson's disease, osteoarthritis,glomerulonephritis, interstitial nephritis, Lupus nephritis, tubularnecrosis, diabetic nephropathy, or renal hypertrophy. In some instances,Fms selectivity of compounds in combination with the compounds inabilityto cross the blood brain barrier provides preferred activity fortreating certain diseases, such as osteoarthritis, glomerulonephritis,interstitial nephritis, Lupus nephritis, tubular necrosis, diabeticnephropathy, or renal hypertrophy. In some instances, Fms selectivity ofcompounds in combination with the compounds ability to effectively crossthe blood brain barrier provides preferred activity for treating certaindiseases, such as rheumatoid arthritis, Alzheimer's disease, orParkinson's disease. In some instances, dual Fms/Kit activity providespreferred activity for treating certain diseases, such as breast cancer,prostate cancer, multiple myeloma, melanoma, acute myeloid leukemia,brain metastases, neurofibromatosis, gastrointestinal stromal tumors,rheumatoid arthritis, or multiple sclerosis. In some instances, dualFms/Flt-3 activity provides preferred activity for treating certaindiseases, such as acute myeloid leukemia. In addition to demonstratingkinase inhibitory activity against Fms, Kit, Flt-3 or at least both Fmsand Kit or at least both Fms and Flt-3 in both biochemical and cellbased assays, compounds have improved solubility, improvedpharmacokinetic properties, and low Cyp inhibition. The compounds areassessed in the following assays or similar assays available to oneskilled in the art.

Assays for biochemical and cell based activity are known in the art, forexample, U.S. Patent Application Publication Number 2009/0076046, thedisclosure of which is hereby incorporated by reference as it relates tosuch assays. For example, in one assay the biochemical activity IC₅₀values are determined with respect to inhibition of c-Kit kinaseactivity, where inhibition of phosphorylation of a peptide substrate ismeasured as a function of compound concentration. Compounds to be testedare dissolved in DMSO to a concentration of 20 mM. These are diluted 30μL into 120 μL of DMSO (4 mM) and 1 μL is added to an assay plate. Theseare then serially diluted 1:2 (50 μL to 100 μL DMSO) for a total of 8points. Plates are prepared such that each kinase reaction is 20 μL in1× kinase buffer (25 mM HEPES, pH 7.5, 2 mM MgCl₂, 2 mM MnCl₂, 0.01%Tween-20, 1 mM DTT, 0.01% BSA), 5% DMSO and 100 μM ATP. Substrate is 30nM biotin-(E4Y)10 (Millipore). C-kit kinase (obtained from Millipore(#14-559) or is prepared as described in U.S. Patent ApplicationPublication Number 2009/0076046, the disclosure of which is herebyincorporated by reference as it relates to this assay) is at 0.75 ng persample. After incubation of the kinase reaction for 1 hour at roomtemperature, 5 μL of donor beads (Streptavidin coated beads (PerkinElmer Life Science) final concentration 10 μg/mL) in stop buffer (25 mMHepes pH 7.5, 100 mM EDTA, 0.01% BSA) is added, the sample is mixed andincubated for 20 minutes at room temperature before adding 5 μL ofacceptor beads (PY20 coated beads (Perkin Elmer Life Science) finalconcentration 10 μg/mL) in stop buffer. The samples are incubated for 60minutes at room temperature and the signal per well is read on Envisionreader. Phosphorylated substrate results in binding of the PY20 antibodyand association of the donor and acceptor beads such that signalcorrelates with kinase activity. The signal vs. compound concentrationis used to determine the IC₅₀.

In one assay the biochemical activity IC₅₀ values are determined withrespect to inhibition of Fms kinase activity, where inhibition ofphosphorylation of a peptide substrate is measured as a function ofcompound concentration. Compounds to be tested, dissolved in DMSO (1μL), are added to a white 384-well plate (Costar #3705). Working stocksof Fms kinase (Invitrogen #PV3249), biotin-(E4Y)₁₀ substrate (UpstateBiotech, Cat#12-440), and ATP (Sigma, Cat#A-3377) are prepared in 25 mMHepes pH 7.5, 0.5 mM MgCl₂, 2 mM MnCl₂, 2 mM DTT, 0.01% BSA, and 0.01%Tween-20. All components are added to the 384-well plate for a finalconcentration of 1 ng/well Fms, 30 nM biotin-(E4Y)₁₀ (UpstateBiotechnology) and 100 μM ATP in a volume of 20 μL. Each sample is at 5%DMSO. The plate is then incubated for 20 minutes at 30° C. Just beforeuse, working stocks of donor and acceptor beads from the AlphaScreenPY20 Detection Kit (PerkinElmer, Cat#676601M) are prepared in 25 mMHepes pH 7.5, pH 7.4, 100 mM EDTA, 0.01% BSA. To stop the reaction, theplate is uncovered in the dark and 5 μL of Donor Beads solution(Streptavidin beads) is added to each well. The plate is incubated atroom temperature for 20 minutes. Five microliters of Acceptor Beadssolution (PY20 coated beads) are then added to each well. The finalconcentration of each bead is 10 μg/mL. The plates are incubated at roomtemperature for 60 minutes. Fluorescence signal is recorded on theEnvision reader. Phosphorylated substrate results in binding of the PY20antibody and association of the donor and acceptor beads such thatsignal correlates with kinase activity. The signal vs. compoundconcentration is used to determine the IC₅₀.

In one assay the biochemical activity IC₅₀ values are determined withrespect to inhibition of Flt-3 kinase activity, where inhibition ofphosphorylation of a peptide substrate is measured as a function ofcompound concentration. Compounds to be tested, dissolved in DMSO (1 areadded to a white 384-well plate (Costar #3705). Working stocks of Flt-3kinase (Invitrogen), biotin-(E4Y)₁₀ substrate (Upstate Biotech,Cat#12-440), and ATP (Sigma, Cat#A-3377) are prepared in 25 mM Hepes pH7.5, 5 mM MgCl₂, 5 mM MnCl₂, 1 mM DTT, and 0.01% Tween-20. Allcomponents are added to the 384-well plate for a final concentration of1 ng/well Flt-3, 30 nM biotin-(E4Y)₁₀ and 100 μM ATP in a volume of 20μL. Each sample is at 5% DMSO. The plate is then incubated for 1 hour atroom temperature. Just before use, working stocks of donor and acceptorbeads from the AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M)are prepared in 25 mM Hepes pH 7.5, pH 7.4, 100 mM EDTA. 0.3% BSA. Tostop the reaction, the plate is uncovered in the dark and 5 μL of DonorBeads solution (Streptavidin beads) is added to each well. The plate isincubated at room temperature for 20 minutes. Five microliters ofAcceptor Beads solution (PY20 coated beads) are then added to each well.The final concentration of each bead is 10 μg/mL. The plates areincubated at room temperature for 60 minutes. Fluorescence signal isrecorded on the Envision reader. Phosphorylated substrate results inbinding of the PY20 antibody and association of the donor and acceptorbeads such that signal correlates with kinase activity. The signal vs.compound concentration is used to determine the IC₅₀.

In one assay the biochemical activity IC₅₀ values are determined withrespect to inhibition of TrkA kinase activity, where inhibition ofphosphorylation of a peptide substrate is measured as a function ofcompound concentration. Compounds to be tested, dissolved in DMSO (1μL), are added to a white 384-well plate (Costar #3705). Working stocksof TrkA kinase (UBI), biotin-(E4Y)₁₀ substrate (Upstate Biotech,Cat#12-440), and ATP (Sigma, Cat#A-3377) are prepared in 25 mM Hepes pH7.5, 10 mM MnCl₂, 1 mM DTT, 0.01% BSA, and 0.01% Tween-20. Allcomponents are added to the 384-well plate for a final concentration of1 ng/well TrkA, 30 nM biotin-(E4Y)₁₀ and 100 μM ATP in a volume of 20μL. Each sample is at 5% DMSO. The plate is shaken for 1 minute at 1200rpm, spun for 1 minute at 1000 rpm, then incubated for 40 minutes atroom temperature. Just before use, working stocks of donor and acceptorbeads from the AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M)are prepared in 25 mM Hepes pH 7.5, 100 mM EDTA. 0.01% BSA. Donor Beadssolution (Streptavidin beads) is added (5 μL) to each well to final beadconcentration of 10 μg/mL. The plate is incubated at room temperaturefor 20 minutes. Acceptor Beads solution (PY20 coated beads) are thenadded to each well (5 μL) to a final concentration of bead at 10 μg/mL.The plates are incubated at room temperature for 60 minutes.Fluorescence signal is recorded on the Envision reader. Phosphorylatedsubstrate results in binding of the PY20 antibody and association of thedonor and acceptor beads such that signal correlates with kinaseactivity. The signal vs. compound concentration is used to determine theIC₅₀. Similar assays are used for TrkB and Trk C kinase.

Compounds are assessed in a variety of cell based assays. For exampleBaF3 cells engineered with any of BCR-FMS, BCR-KIT, BCR-FLT3, BCR-NTRK1,BCR-NTRK2, and BCR-NTRK3, are used in cell proliferation assays toassess inhibitory activity of Fms, Kit, Flt-3, TrkA, TrkB, and TrkC,respectively. An MV-4-11 (leukemia) cell proliferation assay is used toassess inhibitory activity in Flt-3, and SKNSH (human neuroblastoma)cell proliferation assay is used to assess efficacy of Fms/Trkinhibitors. Additional cells may be assayed similarly to assess theefficacy of Fms/Trk inhibitors, such as MiaPaCa (human pancreaticcancer) and Capan-1 (human pancreatic carcinoma) cells. Reagent andassay conditions are as follows:

BaF3 Cells:

-   -   Maintained in RPMI containing 10% FBS, 1% PenStrep, 1% NEAA, and        1% L-Glutamine, supplemented with 1 mg/mL G418 and 5% WEHI-CM        (or recombinant murine IL-3).    -   Confluent cells are split 1:50 to 1:100 every 3-4 days.    -   MV-4-11 cells:    -   Maintained in Iscove's Modified Dulbecco's Medium containing 10%        FBS.    -   Confluent cells are split 1:4 every 3-4 days.    -   SKNSH cells: RPMI containing 10% FBS.        On day 1, cells are counted, then centrifuged in a conical tube        for 5 minutes at 1000 rpm. The supernatant is removed and cells        are re-suspended as follows:    -   BaF3: resuspend in growth media+1 mg/mL G418 (without WEHI/IL-3)        to 2×10⁵ cells/mL.    -   MV-4-11: resuspend in growth media to 5×10⁵ cells/mL.    -   SKNSH: resuspend in growth media to 2×10⁴ cells/mL.        The cells are plated (50 μL, 150 μL for SKNSH cells) in each        well of a 96-well dish (Corning 3610) and incubated at 37° C. in        5% CO₂ overnight, cells plated to a final concentration of cells        as follows:

BaF3: 10,000 cells per well.

MV-4-11: 25,000 cells per well.

SKNSH: 3,000 cells per well.

On day 2, compound at a maximum concentration of 5 mM is seriallydiluted 1:3 for a total of 8 point titration with DMSO as a control. A 1μL aliquot of each dilution point is added to 249 μL growth media and 50μL is added to a well containing cells, providing 10 μM compound for themaximum concentration point. The cells are incubated for 3 days at 37°C. in 5% CO₂. For SKNSH cells, a 0.75 μL aliquot of appropriate dilutionin DMSO is added to 150 μL of cells.On day 5, ATPlite 1 step Luminescence Assay System (Perkin Elmer#6016739) is brought to room temperature along with the cell cultures.ATPlite is added to each well as follows:

BaF3: 25 μL per well.

MV-4-11: 40 μL per well.

SKNSH: 20 μL per well.

The cells are incubated at room temperature for 10 minutes, thenluminescence is read on Safire reader. The measured luminescencecorrelates directly with cell number, such that the reading as afunction of compound concentration is used to determine the IC₅₀ value.

Further, an osteoclast differentiation assay is used to assess theefficacy of Fms inhibitors for treating bone disease such asosteoarthritis. On day 0, Osteoclast Medium BulletKit (Lonza catalog #PT-8001, containing Media, FBS, L-Glutamine, PenStrep, RANKL, and M-CSF)media is thawed and the FBS, L-glutamine and PenStrep from the kit isadded to 100 mL of Osteoclast Precursor Basal medium to provide theOsteoclast Precursor Growth Medium (OPGM). This is warmed to 37° C.Osteoclast precursor cells (Lonza catalog #2T-110) frozen in cryovialare warmed to 37° C. and transferred to a 50 mL conical tube. Thecryovial is rinsed with OPGM and added dropwise to the conical tube ofcells with swirling, then the volume is adjusted to 20-30 mL withaddition of OPGM. The cells are centrifuged at 200×g for 15 minutes atroom temperature and all but approximately 3 mL of supernatant isremoved to a new conical tube. The cells are suspended in the remainingsupernatant and the volume is adjusted to 10-15 mL with OPGM addeddropwise with swirling. The cells are centrifuged at 200×g for 15minutes at room temperature and all but approximately 1 mL ofsupernatant is removed. The cells are resuspended in the remainingsupernatant, counted, and the volume adjusted with an appropriate amountof OPGM to provide approximately 1×10⁵ cells/mL. A 0.1 mL aliquot ofcells is added to each well of a 96-well plate. Compound to be tested isprepared in DMSO for plating at a high concentration of 2.5 mM, with 8point 1:3 serial dilutions. A 1 μL aliquot of each compound dilution isadded to a 96 well v-bottom polypropylene plate and 0.124 mL of OPGM isadded to the compound. Then 50 μL of the compound in OPGM is added tothe osteoclast precursor cells in 96-well plate (providing highest testconcentration of 5 RANKL (2 μg) from the BulletKit is reconstituted in 1mL of OPGM, then vortexed and centrifuged briefly. A 792 μL aliquot ofRANKL is added to 6 mL of OPGM and 50 μL is added to low control wells.Then 76.6 μL M-CSF (10 μg/mL) from the BulletKit is added to theremaining 5.8 mL of OPGM/RANKL solution (4×RANKL/M-CSF/OPGM). A 50 μLaliquot of this is added to the remaining wells, and the remainder isstored at 4° C. for later use. The plate is incubated at 37° C. for 6days, then the remaining OPGM/RANKL/M-CSF solution is warmed to 37° C.The remaining approximately 198 μL is combined with 6 mL of OPGM. Themedia is aspirated from the osteoclast wells and 100 μL of RANKL/OPGM isadded to the low controls. The remaining RANKL/OPGM is combined with theapproximately 18.5 μL of remaining M-CSF. The remaining4×RANKL/M-CSF/OPGM from day 0 is diluted to 1× and combined with thefreshly prepared solution. A 0.1 mL aliquot of this is added to eachosteoclast well and incubated for 37° C. for 1 day. The Acid Phosphatasekit (Cayman Chemical catalog #10008051) is warmed to room temperature.The assay buffer is diluted 5 mL with 45 mL of water. For each plate,two substrate tablets are dissolved in 4.5 mL of the assay buffer,mixing by vortex to break up the tablet. Stop solution is diluted 12 mLwith 36 mL of water. In a tissue culture hood, 20 μL of each osteoclastwell supernatant is transferred to a 96 well plate. A 30 μL aliquot ofthe substrate solution is added to each well and incubated at 37° C. for20 minutes, then added 100 μL stop solution to each well. The absorbanceof each well is read at 405 nM on Safire plate reader. The absorbancereading is plotted vs. concentration to provide the IC₅₀ for eachcompound.

It is understood that the results of these assays may vary as assayconditions are varied. Inhibition levels determined under the conditionsdescribed herein represent a relative activity for the compounds testedunder the specific conditions employed. The cell based assays are likelyto show variability due to the complexity of the system and thesensitivity thereof to any changes in the assay conditions. As such,some level of inhibition in the cell based assays is indicative of thecompounds having some inhibitory activity for those cells, whereas lackof inhibition at or below the threshold of the highest concentrationtested does not necessarily indicate that the compound has no inhibitoryactivity on the cells, only that under the conditions tested, noinhibition is observed. Results for compounds that are tested and showsubstantially no inhibition below the highest tested concentration arerepresented as “-” in the tables below. In some instances, the compoundswere not tested in all of the assays, or assay results were not valid,as indicated by NA in the tables below.

The following table indicates the Fms, Kit, Flt3, TrkA, and TrkCbiochemical inhibitory activity for the exemplary compounds indicated:

Compound Biochemical Inhibition IC₅₀ (μM) number Fms Kit Flt3 TrkA TrkCP-3001 <0.1 <1 NA NA NA P-3003 <1 >1 NA NA NA P-3004 <0.01 <1 >1 NA NAP-3005 <1 >1 NA NA NA P-3006 <0.01 <1 NA NA NA P-3007 <1 >1 NA NA NAP-3008 <0.1 <1 NA NA NA P-3009 <0.1 NA NA NA NA P-3010 <0.01 <0.1 <0.1<1 NA P-3011 <0.01 <0.01 <0.01 >1 NA P-3012 <0.01 <0.01 <0.1 >1 NAP-3013 <0.01 <1 >1 NA NA P-3014 <0.01 <0.1 <1 >1 NA P-3015 <0.01 <1<0.1 >1 NA P-3016 <0.1 <0.1 <0.1 >1 NA P-3017 <0.1 <1 <0.1 >1 NA P-3018<0.01 <0.01 <0.01 <1 NA P-3019 <0.01 <1 <1 <0.1 <0.1 P-3020 <0.01 <0.01<0.01 <0.1 <1 P-3021 <0.01 <0.01 <0.01 <0.1 <1 P-3022 <0.1 <0.1 <0.1 <1<1 P-3023 <0.1 <0.1 NA NA NA P-3024 <0.1 <0.01 <0.01 <1 >1 P-3025 <0.1<0.01 <0.01 <0.1 <0.01 P-3026 <0.01 <0.01 <0.1 >1 <0.1 P-3027 <0.01<0.01 <0.01 <1 <0.1 P-3028 >1 <1 NA <0.1 <0.1 P-3029 <0.1 <1 NA <1 <1P-3030 <0.1 <0.1 NA <0.01 <0.01 P-3031 <1 <0.1 NA <0.1 <0.1 P-3032 >1 <1NA >1 >1 P-3033 <0.1 <0.01 NA <0.01 <0.1 P-3034 <0.1 <0.1 NA <1 <1P-3035 <1 <0.1 <0.1 <1 <1 P-3036 <0.01 <0.1 <0.1 <1 <1 P-3037 >1 <1 NANA NA P-3038 <1 <1 NA NA NA P-3039 <0.01 <0.1 <0.1 <0.1 NA P-3040<0.1 >1 <0.1 <0.01 NA P-3041 <0.01 <1 <1 <1 NA P-3042 <0.01 <0.1 <1 <0.1NA P-3043 <0.01 <1 <1 <0.1 NA P-3044 <0.01 <1 <1 <0.1 NA P-3045 <0.01 <1<0.1 <0.01 NA P-3048 <0.01 <0.1 NA <0.01 NA P-3049 <0.01 <0.1 NA <0.01NA P-3050 <0.1 <0.1 NA <0.1 NA P-3051 <0.01 <0.1 NA <0.01 NA P-3052 <0.1<0.1 NA <0.01 NA P-3053 <0.01 <0.1 NA <0.1 NA P-4001 <0.01 <1 <1 <0.1<0.01 P-4002 <0.1 <1 NA <0.1 <1 P-4003 <0.1 <1 <1 <1 NA P-4004 <0.1 <0.1<0.01 <0.1 NA P-4005 <0.01 <0.1 <0.1 <0.1 NA P-4006 <0.01 <0.1 <0.1 <0.1NA P-4007 <0.01 <0.1 <0.1 <0.01 NA P-4008 <0.01 <1 <0.1 <0.01 NA P-4009<0.01 <0.1 <0.1 <0.01 NA P-4010 <0.01 <1 <1 <1 NA P-4011 <0.01 <1 <1 <1NA P-4012 <0.01 <1 <1 <0.1 NA P-4013 <0.01 <1 >1 <1 NA P-4014 <0.01 <0.1<1 >1 NA P-4015 <0.1 <0.1 >1 >1 NA P-4016 <0.01 <0.1 <0.01 <0.01 NAP-4017 <0.01 <0.1 <0.1 <0.1 NA P-4018 <0.01 <0.1 <0.1 <0.1 NA P-4019<0.01 <1 <0.1 <0.1 NA P-4020 <0.01 <0.1 <0.1 <0.01 NA P-4021 <0.1 <1 >1<1 NA P-4022 <0.1 <1 <0.1 <0.01 NA P-4023 <0.01 <1 <1 <0.1 NA P-4024 <1<1 <0.1 <0.1 NA P-4025 <1 >1 <1 <0.1 NA P-4026 <0.01 <1 <0.1 <0.01 NAP-4027 <0.1 <0.1 <0.01 <0.01 NA P-4028 <0.01 <0.1 <0.1 <0.01 NA P-4029<0.01 <0.1 <0.01 <0.01 NA P-4030 <0.01 <1 <1 <0.1 NA P-4031 <0.1 <0.1<0.1 <0.1 NA P-4032 <0.1 <0.1 <0.1 <0.1 NA P-4036 <0.01 <1 >1 <0.1 NAP-4037 <0.1 <1 <1 <0.1 NA P-4038 <0.1 <1 NA <0.1 NA P-4039 <1 <1 NA <0.1NA P-4040 <0.1 <0.1 NA <0.01 NA P-4041 <0.1 <0.1 NA <0.01 NA P-4046 <0.1<1 NA <1 NA P-4047 >1 >1 NA >1 NA P-4048 <0.01 <0.01 NA <0.01 NA P-4049<0.01 <1 NA <0.01 NA P-4050 <1 <1 NA <1 NA P-4051 <1 <1 NA <0.01 NAP-4052 <1 >1 NA <1 NA P-4053 <0.01 <1 NA <0.01 NA P-4054 <0.01 >1 NA<0.1 NA P-4055 <0.1 <1 NA NA NA P-4056 <0.1 <0.1 NA NA NA P-4057 <0.1 >1NA <1 NA P-4058 <0.1 >1 NA <1 NA P-4059 <0.1 <1 NA <0.1 NA P-4060 <0.01<0.1 NA <0.01 NA P-4061 <0.1 >1 NA <0.1 NA P-4062 <0.01 <0.1 NA <0.01 NAP-4063 <0.01 <1 NA <0.01 NA P-4064 <0.01 <0.1 NA <0.01 NA P-4065 <0.01<0.1 NA <0.01 NA P-4066 <0.01 <0.1 NA <0.01 NA P-4067 <0.01 <1 NA <0.01NA P-4068 <0.01 <0.1 NA <0.01 NA P-4069 <1 >1 NA <0.1 NA P-4070 >1 >1NA >1 NA P-4071 <1 >1 NA <0.01 NA P-4072 <0.1 >1 NA <0.1 NA P-4073 <0.1<1 NA <0.01 NA P-4074 <0.1 <1 NA <0.01 NA P-4075 <0.01 <1 NA <0.01 NAP-4076 <0.01 <0.1 NA <0.01 NA P-4077 <0.1 <1 NA <0.01 NA P-4078 <0.01 <1NA <0.01 NA P-4079 <0.01 <0.1 NA <0.01 NA P-4080 <0.01 <1 NA <0.01 NAP-4081 <0.01 <0.1 NA <0.01 NA P-4082 <0.1 <1 NA <0.01 NA P-4083 <0.01<0.1 NA <0.01 NA P-4084 <0.01 <0.1 NA <0.01 NA P-4085 <0.01 <1 NA <0.01NA P-4086 <1 <1 NA <0.1 NA P-4087 <0.1 <0.1 NA <0.01 NA P-4088 <0.1 <1NA <0.01 NA P-4089 <0.1 <1 NA <0.1 NA P-4090 <0.1 <1 NA <0.1 NA P-4091<0.1 <0.1 NA <0.01 NA P-4092 <0.01 <0.1 NA <0.01 NA P-4093 <0.01 <0.1 NA<0.01 NA P-4094 <0.01 <0.01 NA <0.01 NA P-4095 <0.01 <0.1 NA <0.01 NAP-4096 <0.1 <1 NA <0.1 NA P-4097 <1 <1 NA <0.1 NA P-4098 <0.01 <0.1 NA<0.01 NA P-4099 <0.1 <0.1 NA <0.1 NA P-4100 <0.1 <0.1 NA <0.1 NA P-4101<0.1 <1 NA <0.1 NA P-4102 <0.1 <1 NA <0.1 NA P-4103 <1 <1 NA <0.1 NAP-4104 <1 <1 NA <0.1 NA P-4105 <0.1 >1 NA <0.1 NA P-4106 <0.1 <1 NA<0.01 NA P-4107 <0.1 <0.1 NA <0.01 NA P-4108 <0.1 <1 NA <0.1 NA P-4109<0.1 <1 NA <0.1 NA P-4110 <0.1 <1 NA <1 NA P-4111 <0.1 <1 NA <0.1 NAP-4112 <0.1 <1 NA <0.1 NA P-4113 <0.01 <0.1 NA <0.01 NA P-4114 <0.01<0.1 NA <0.01 NA P-4115 <0.01 <0.1 NA <0.01 NA P-4116 <0.1 <0.1 NA <0.01NA P-4117 <0.01 <0.1 NA <0.01 NA P-4118 <0.1 <0.1 NA <0.01 NA P-4119<0.01 <0.01 NA <0.01 NA P-4120 <0.1 <0.1 NA <0.1 NA P-4121 <0.1 <0.01 NA<0.1 NA P-4122 <0.01 <0.01 NA <0.01 NA P-4123 <0.01 <0.01 NA <0.01 NAP-4124 <0.01 <0.01 NA <0.01 NA P-4125 <0.1 <0.1 NA <0.01 NA P-4126 <0.01<0.1 NA <0.01 NA P-4127 <0.1 <1 NA <0.1 NA P-4128 <0.1 >1 NA <1 NAP-4129 <0.1 <1 NA <1 NA P-4130 <0.01 <1 NA <0.01 NA

The following table indicates the inhibition of cell proliferation forBCR-FMS, BCR-KIT, BCR-FLT3, BCR-NTRK1, BCR-NTRK2 and BCR-NTRK3 BaF3cells, MV-4-11 cells and SKNSH cells for the exemplary compoundsindicated:

Inhibition of Cell Proliferation IC₅₀ (μM) Comp. BCR/BaF3 number Fms KitTrkA TrkB TrkC MV-4-11 SKNSH P-3001 <0.1 >1 — — — NA NA P-3003 <1 >1 NANA NA NA NA P-3004 <0.1 >1 <10 <10 <10 <10 NA P-3005 <1 >1 — — — NA NAP-3006 <1 >1 <20 — — NA NA P-3007 <1 — — — — NA NA P-3008 <0.1 >1 NA NANA NA NA P-3009 <1 >1 — — — NA NA P-3010 <0.1 <1 — — — NA NA P-3011 <0.1<0.1 <1 <1 <0.1 NA NA P-3012 <0.1 <1 <1 <1 <1 NA NA P-3013 <0.1 >1 — — —<10 NA P-3014 <0.1 >1 — — — NA NA P-3015 <1 >1 — — — NA NA P-3016 <1 >1— — — NA NA P-3017 <1 >1 — — — NA NA P-3018 <0.1 <0.1 <1 <0.1 <0.1 <0.01NA P-3019 <0.01 <1 <0.1 <0.1 <0.1 <1 <10 P-3020 <0.01 <0.1 <0.1 <0.1<0.1 <0.1 <1 P-3021 <0.01 <0.1 <1 <0.1 <0.1 NA <1 P-3022 <0.1 <0.1 <1 <1<1 <1 NA P-3023 <0.1 <0.1 <1 <1 <1 <0.1 NA P-3024 <0.01 <0.1 <1 <1 <0.1NA <1 P-3025 <0.01 <0.01 <0.01 <0.01 <0.01 NA <1 P-3026 <0.01 <0.1 <0.1<0.1 <0.1 NA — P-3027 <0.01 <0.1 <0.1 <1 <0.1 <0.01 — P-3028 <1 <0.1<0.1 <1 <0.1 NA <20 P-3029 <0.1 <1 >1 >1 <1 NA — P-3030 <0.01 <0.01<0.01 <0.01 <0.01 NA <0.1 P-3031 <0.01 <0.01 <0.01 <0.01 <0.01 NA <0.1P-3032 <1 <1 <1 >1 <1 NA <1 P-3033 <0.01 <0.01 <0.1 <0.1 <0.1 NA <1P-3034 <0.01 <0.1 <0.1 <1 <0.1 NA <1 P-3035 <0.1 <1 <1 <1 <0.1 <1 <1P-3036 <0.01 <0.1 <1 <1 <1 <0.1 <20 P-3037 >1 >1 >1 — >1 NA — P-3038 <1<1 <1 >1 <1 >1 — P-3039 <0.01 <1 <1 <1 <0.1 <1 >1 P-3040 <0.1 >1 <0.1<0.01 <0.01 NA >1 P-3041 <0.01 <1 <1 <1 <0.1 NA >1 P-3042 <0.1 <1 <1<0.1 <0.1 NA >1 P-3043 <0.1 <1 <0.1 <0.1 <0.1 NA <1 P-3044 <0.1 <1 <1<0.1 <0.1 NA >1 P-3045 <0.1 <1 <0.1 <0.01 <0.1 NA — P-3048 <0.01 <0.1<0.1 NA NA NA NA P-3049 <0.01 <0.1 <0.01 NA NA NA NA P-3050 <0.1 <1 <0.1NA NA NA NA P-3051 <0.1 <1 <0.1 NA NA NA NA P-3052 <0.1 NA <0.1 NA <0.01NA NA P-3053 <0.01 NA <0.1 NA <0.01 NA NA P-4001 <0.01 <1 <0.1 <0.1<0.01 <1 <1 P-4002 <0.1 <1 <1 <1 <0.1 NA <0.1 P-4003 <0.1 >1 <1 <1 <0.1<1 >1 P-4004 <0.01 <0.1 <0.01 <0.01 <0.01 <1 <1 P-4005 <0.01 <0.1 <0.1<0.01 <0.01 <1 <1 P-4006 <0.01 <0.1 <0.1 <0.01 <0.01 <0.1 <0.1 P-4007<0.01 <1 <0.01 <0.1 <0.01 <1 <1 P-4008 <0.01 <1 <0.1 <0.1 <0.1 <0.1 >1P-4009 <0.01 <1 <0.1 <0.01 <0.01 <0.1 <0.1 P-4010 <0.01 <1 <1 <0.1 <0.1<1 <1 P-4011 <0.01 >1 <1 <1 <1 <1 >1 P-4012 <0.01 <1 <1 <0.1 <0.1 <1 >1P-4013 <0.01 <1 <1 <1 <1 <1 >1 P-4014 <0.1 >1 <1 <1 <1 <1 >10 P-4015<0.01 >1 <1 <1 <0.1 <1 >1 P-4016 <0.01 <0.1 <0.1 <0.01 <0.01 <0.1 >1P-4017 <0.01 <1 <1 <1 <0.1 <1 <1 P-4018 <0.01 <1 <0.1 <0.1 <0.01 <1 <1P-4019 <0.01 <1 <1 <0.1 <0.1 <1 >1 P-4020 <0.1 <1 <1 <0.1 <0.1 NA <1P-4021 <1 >1 >1 <1 <1 NA <1 P-4022 <0.1 <1 <0.01 <0.01 <0.01 NA <1P-4023 <0.01 <1 <0.1 <0.1 <0.01 NA <1 P-4024 <0.1 <1 <0.1 <0.1 <0.1NA >1 P-4025 <0.1 >1 <0.1 <0.1 <0.1 NA >1 P-4026 <0.01 <1 <0.1 <0.01<0.01 NA NA P-4027 <0.1 <1 <0.1 <0.01 <0.01 NA NA P-4028 <0.01 <1 <0.01<0.01 <0.01 NA NA P-4029 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA P-4030 <0.01<1 <1 <0.1 <0.1 NA NA P-4031 <0.1 <1 <0.1 <0.01 <0.01 NA NA P-4032 <0.1<1 <0.1 <0.1 <0.1 NA NA P-4036 <0.1 <1 <1 <0.1 <0.1 NA NA P-4037 <0.1<0.1 <0.1 NA NA NA NA P-4038 <0.1 <1 <1 <1 <0.1 NA NA P-4039 <0.1 <1<0.1 <0.1 <0.1 NA NA P-4040 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA P-4041<0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4046 <0.1 <1 <1 <1 <1 NA <10P-4047 >1 >1 >1 >1 >1 NA NA P-4048 <0.01 <1 <1 <0.01 <0.01 NA <1 P-4049<1 <1 <1 <1 <1 NA <1 P-4050 <1 >1 <1 <1 <1 NA <1 P-4051 <1 >1 <1 <0.01<0.01 NA <1 P-4052 <1 >1 <1 <1 <0.01 NA >1 P-4053 <1 <1 <0.01 <0.01<0.01 NA <1 P-4054 <1 <1 <1 <1 <0.01 NA <10 P-4055 <1 >1 <1 <0.01 <0.01NA <1 P-4056 <1 >1 <1 <0.01 <0.01 NA <1 P-4057 <1 >1 >1 >1 <1 NA <10P-4058 <0.1 <1 <1 <1 <0.1 NA <10 P-4059 <0.1 >1 <1 <0.1 <0.1 NA <1P-4060 <0.01 <0.1 <0.01 <0.01 <0.01 NA <0.1 P-4061 <0.1 >1 <0.1 <0.01<0.01 NA NA P-4062 <0.1 <1 <0.01 <0.01 <0.01 NA <1 P-4063 <0.1 <0.1<0.01 <0.1 <0.01 NA <1 P-4064 <0.1 <0.1 <0.1 <0.01 <0.01 NA NA P-4065<0.1 <0.1 <0.1 <0.01 <0.01 NA <1 P-4066 <0.01 <0.01 <0.01 <0.01 <0.01 NANA P-4067 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4068 <0.01 <0.1 <0.01<0.01 <0.01 NA NA P-4069 >1 >1 >1 >1 >1 NA NA P-4070 >1 >1 >1 >1 >1 NANA P-4071 <0.1 <0.1 <0.1 <0.1 <0.01 NA NA P-4072 <0.1 <1 <0.01 <0.01<0.01 NA NA P-4073 <0.1 <1 <0.1 <0.01 <0.01 NA NA P-4074 <1 <1 <0.1 <0.1<0.01 NA NA P-4075 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4076 <0.1 <0.1<0.01 <0.01 <0.01 NA NA P-4077 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4078<0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4079 <0.1 <0.1 <0.01 <0.01 <0.01 NANA P-4080 <0.1 <0.1 <0.01 <0.01 <0.01 NA NA P-4081 <0.01 <0.1 <0.01<0.01 <0.01 NA NA P-4082 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4083 <0.1<0.1 <0.01 <0.01 <0.01 NA NA P-4084 <0.01 <1 <0.1 <0.01 <0.01 NA <10P-4085 <1 >1 <1 NA <0.1 NA NA P-4086 NA NA <0.01 NA NA NA NA P-4087<1 >1 <1 <0.1 <0.01 NA NA P-4088 <0.1 <1 <0.1 <0.1 <0.01 NA NA P-4089<0.1 <1 <1 <0.1 <0.01 NA <10 P-4090 <0.1 <1 <0.1 <0.01 <0.01 NA <1P-4091 <0.01 <0.1 <0.01 <0.01 <0.01 NA <0.1 P-4092 <0.01 <0.1 <0.01<0.01 <0.01 NA <1 P-4093 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4094 <0.1<0.1 <0.01 <0.01 <0.01 NA <1 P-4095 <0.01 <0.1 <0.01 <0.01 <0.01 NA <1P-4096 <0.01 <1 <0.01 <0.01 NA NA <10 P-4097 <0.1 <1 <0.1 <0.1 NA NA <10P-4098 <0.1 <0.1 <0.01 <0.01 NA NA <10 P-4099 <0.01 <0.1 <0.01 <0.01 NANA <1 P-4100 <0.1 <1 <0.01 <0.01 NA NA <1 P-4101 <0.01 <1 <0.1 <0.01 NANA <1 P-4102 <0.01 <1 <1 <0.1 NA NA <1 P-4103 <0.1 >1 <1 >1 >1 NA >1P-4104 <0.1 >1 <0.1 <0.1 <0.1 NA <1 P-4105 <0.1 >1 <0.1 <1 <1 NA <10P-4106 <0.1 <1 <0.1 <0.1 <0.01 NA <1 P-4107 <0.1 <1 <0.1 <0.1 <0.01 NA<1 P-4108 <0.1 >1 <1 <1 <0.1 NA >1 P-4109 <0.1 <1 <1 <1 NA NA <10 P-4110<0.1 <1 >1 >1 NA NA <10 P-4111 <0.1 <1 <0.01 <0.01 <0.01 NA NA P-4112<0.1 >1 <0.1 <0.1 <0.01 NA <10 P-4113 <0.01 <1 <0.1 NA NA NA NA P-4114<0.01 <1 <0.01 NA NA NA NA P-4115 <0.01 <1 <0.1 <0.1 <0.01 NA NA P-4116<0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4117 <0.01 <0.1 <0.01 <0.01 <0.01NA NA P-4118 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4119 <0.01 <0.1 <0.01<0.01 <0.01 NA NA P-4120 <0.1 <1 <0.01 <0.01 <0.01 NA <1 P-4121 <0.01<0.1 <0.01 <0.01 <0.01 NA NA P-4122 <0.01 <0.1 <0.01 <0.01 <0.01 NA NAP-4123 <0.01 <0.1 <0.01 <0.01 <0.01 NA <0.1 P-4124 <0.01 <0.1 <0.01<0.01 <0.01 NA <1 P-4125 <0.01 <0.1 <0.01 <0.01 <0.01 NA NA P-4126 <0.01<0.1 <0.01 <0.01 <0.01 NA <0.1 P-4127 <0.01 <0.1 <1 <0.1 <0.1 NA <10P-4128 <0.1 <1 <1 <0.1 <0.1 NA >1 P-4129 <0.1 <1 <1 <0.1 <0.1 NA >10P-4130 <0.01 >1 <0.1 <0.01 <0.01 NA <10

Compounds P-3001, P-3004, P-3006, P-3008, P-3013, P-3019, P-3027,P-3036, P-3039, P-3040, P-3041, P-3042, P-3043, P-3044, P-3045, P-4001,P-4004, P-4005, P-4006, P-4007, P-4008, P-4009, P-4010, P-4011, P-4012,P-4013, P-4014, P-4015, P-4016, P-4017, P-4022, P-4023, P-4024, P-4025,and P-4026 to P-4130 were assessed and showed activity in the osteoclastdifferentiation assay, where compounds P-3004, P-3006, P-3008, P-3019,P-3027, P-3036, P-3039, P-3041, P-3042, P-4001, P-4004, P-4005, P-4006,P-4007, P-4008, P-4009, P-4010, P-4011, P-4012, P-4013, P-4014, P-4015,P-4016, and P-4023 demonstrated an IC₅₀ below 0.1 μM in this assay.

Compounds also demonstrate in vivo activity in a splenomegaly mousemodel, where BaF3 cell growth in the spleens of nude mice may showinhibition with compound treatment. BaF3 cells are engineered with anyof BCR-FMS, BCR-TRK1 or BCR-TRK2 to assess in vivo inhibitory effects ofFms, TrkA or TrkB inhibition, respectively. BaF3 cells are maintained ingrowth media (RPMI containing 10% FBS, 1% PenStrep, 1% NEAA, and 1%L-Glutamine, supplemented with 5% murine IL-3 and 1 mg/mL G418). Fourdays prior to start, 2×10⁶ cells are inoculated into a T150 vented flaskusing the growth media and incubated at 37° C. in 5% CO₂ for three days.One day prior to start, cells are collected by centrifugation and resuspended in growth media without IL-3. On the day of cell implant, thecells are collected by centrifugation, rinsed 3×20 mL with RPMI, then resuspended in 5.4 mL of media and counted, then adjusted with additionalRPMI as needed to give 5×10⁷ cells/mL. On day 1, female nu/nu mice at5-6 weeks of age are injected intravenously with BaF3 cells injectedinjecting 0.1 mL (5×10⁶) cells in the tail vein (mice without cellinjected are included as control group). Compound stocks indimethylsulfoxide are stored at room temperature protected from light.Stocks are diluted prior to dosing, diluting 22 μL of compound stockinto 858 μL of diluent (or 50 μL into 1950 μL) to provide vehicle of1.0% Polysorbate 80, 0.5% hydroxypropyl methyl cellulose, with finaldimethylsulfoxide at 2.5% in all dosing suspensions and vehicle control.Dosing suspension is prepared prior to use, mixing by inversion andsonication in a water bath to make a uniform suspension. On days 10-18,mice are treated with vehicle only or the desired level of compound invehicle, ˜0.2 mL per 25 gm mouse, once a day by oral gavage, or in someinstances, twice per day. On day 18, mice are administered a final doseand two hours later a plasma sample is taken. At four hours followingthe final dose, mice are sacrificed, an additional plasma sample iscollected and mouse spleens are removed and weighed. The average spleenweight of vehicle control group mice is compared to the average spleenweight of the test compound mice. Percent spleen growth inhibition iscalculated as 100×[(spleen weight vehicle control-spleen weight testcompound)/spleen weight vehicle control]. In some instances, thecompounds were not tested in all of the assays as indicated by NA in thetable below.

The following table provides data indicating the percent spleen growthinhibition for exemplary compounds indicated (dosed once per day at 10mg per kg unless indicated otherwise) in the splenomegaly mouse model:

Comp. % spleen growth inhibition number Fms TrkA TrkB P-3004 43 NA NAP-3010 47 NA NA P-3013 48 NA NA P-3019 40 NA 14 P-3027 42 NA  2 P-304511 NA NA P-4004 36 16 41 P-4004* 70 40 91 P-4005 65 25 35 P-4006 55 NA21 P-4007 28 NA 19 P-4012 24 NA NA P-4022 42 NA 33 P-4026 41 NA NAP-4027 −1.4 NA NA P-4028 86 NA 88 P-4029 66 NA NA P-4030 58 NA 50 P-403129 NA NA P-4053 69 NA NA P-4090^(#) 38 NA NA P-4084 6.2 NA NA P-4062 76NA NA P-4061 48 NA NA P-4112 9.5 NA NA P-4110 30 NA NA P-4124 20 NA NAP-4120 37 NA NA P-4123^(#) 14 NA NA P-4130 70 NA NA P-4128 15 NA NA*Dosed at 30 mg/kg. ^(#)Dosed at 5 mg/kg.

As an indication of relative solubility, the turbidity of compounds inaqueous solutions is assessed. To assess possible compound properties indifferent physiological compartments, such as stomach, intestine, andblood, a series of aqueous buffers with varying pH is used. Thus eachcompound is diluted into four different physiologically relevant buffersand solution turbidity is measured by spectrophotometry. Theconcentration of compound that demonstrates turbidity by forming enoughinsoluble suspension to raise the average optical density above 0.01 atthree wavelengths (490, 535, and 650 nm) is used to define the limit ofthe compound solubility in that buffer.

Compounds are dissolved at a concentration of 25 mM in dimethylsulfoxide, then serially diluted 1:1 into a 96 well plate, diluting 10times in pure dimethyl sulfoxide, with the final well of each row adimethyl sulfoxide blank. In an assay plate, 99 μL of appropriate bufferis added to each well, and 1 μL of each sample dilution is added to thebuffer, achieving a range of final total concentrations in aqueoussolutions having different pH. The buffers used are Simulated GastricFluid (SGF-pH 1.5) 0.5M NaCl, pH 1.5; Simulated Intestinal fluid (SIF-pH4.5 and pH 6.8) 0.05M NaH₂PO₄, pH 4.5 and 6.8; and Hepes Buffer(HEPES-pH 7.4) 10 mM HEPES, 150 mM NaCl, pH 7.4. Control compoundspyrene, estriol and propranolol HCl are also assessed. Plates are spunand then mixed for 1 minute, and the absorbance is read using a TecanSafire II to read wavelengths in the visible range (490, 535, and 650nm) at four locations per well, reflecting the degree of turbiditypresent. The average optical density for each wavelength in each well isgraphed vs. compound concentration, and the concentration at which thecurve crosses a threshold O.D. of 0.01 for each wavelength is reportedas the endpoint turbidity assay result. The average of the threewavelengths is used to compare turbidity of compounds. Compounds areconsidered to have low solubility if the threshold concentration is<31.3 μM, moderate solubility if the threshold concentration is 31.3 μMto 250 μM, and high solubility if the threshold concentration is >250μM.

The following table indicates the relative solubility (L=low,M=moderate, H=high) based on turbidity threshold concentration at eachpH for exemplary compounds according to the invention as indicated:

Compound turbidity threshold (L, M, H) number 1.4 4.5 6.8 7.4 P-3001 H LL L P-3004 H L L L P-3010 H L L M P-3011 L L L L P-3012 M M M M P-3013 LL L L P-3014 H M M M P-3018 H M M M P-3019 H L L L P-3039 H M M M P-3040M M M M P-3043 M M M M P-3044 L L L M P-3045 M M M L P-4001 M M M MP-4002 H M M M P-4003 M M M M P-4004 M M L L P-4005 M L L L P-4006 H L LL P-4007 M L L L P-4008 M M M M P-4009 H M L L P-4010 H M L L P-4011 M MM M P-4012 M L L L P-4013 H M M M P-4014 M M M M P-4015 M M M M P-4016 MH M M P-4017 M M M L P-4018 M L L L P-4019 M L L L P-4022 H M L L P-4023H M L L P-4024 M L M M P-4025 M L L L P-4036 H M L L P-4037 H M M MP-4048 H M M M P-4049 H L L L P-4050 H L L L P-4051 H M M L P-4052 L L LL P-4053 H M M M P-4054 H M M M P-4055 M M L L P-4056 M M M L P-4057 L LL M P-4058 M L L L P-4059 M L L L P-4060 H M M M P-4061 M L M M P-4062 HL M L P-4063 M M M M P-4064 H M L L P-4065 H M M M P-4066 M L L M P-4067H M M M P-4068 H M M M P-4069 M L M M P-4070 H M M M P-4071 M M M MP-4072 M L L L P-4073 M L L L P-4074 H M M M P-4075 M L L L P-4076 M M ML P-4077 M L L L P-4078 M L L L P-4079 H M M M P-4080 M M H M P-4081 H MH M P-4082 M L L L P-4083 M M M H P-4084 M M M H P-4087 H M M M P-4088 HM M M P-4089 H M M M P-4090 M M M M P-4091 H M M M P-4092 M M M M P-4093H L L L P-4094 H L M M P-4095 M M M M P-4096 H L L L P-4097 M L L LP-4098 H L M M P-4099 H L L L P-4100 H M M M P-4101 M L L L P-4102 H M MM P-4103 L M M M P-4104 M L L L P-4105 M M M M P-4106 M M L M P-4107 M MM M P-4108 H M M M P-4109 L L L L P-4110 M L L L P-4111 H L L L P-4112 MM M H P-4114 H L L L P-4115 H M M M P-4116 H M M M P-4117 H L L L P-4118H M M L P-4119 H M M L P-4120 L M M M P-4121 H H H H P-4122 H L M LP-4123 H L L L P-4124 M L L M P-4125 H L L L P-4127 H M M M P-4128 H M MM P-4129 H M M M P-4130 H M M M

CYP (Cytochrome P450) enzymes are the major drug metabolizing enzymespresent in the liver. The inhibition of CYP enzyme activity (IC₅₀) foreach of CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4(BFC) and CYP3A4(BQ) isdetermined for compounds, where inhibition of metabolism of a knownsubstrate leads to a decrease in the fluorescence of the metabolizedproduct. The fluorescence of the product is monitored as a function ofcompound concentration.

Compounds are dissolved in DMSO to a concentration of 100 mM. These arediluted 1 into 82 μL of acetonitrile. An 11 μL aliquot of this solutionis then added to 204 μL of cofactor mix (1.3% NADPH Regeneration systemSolution A, 1.04% NADPH Regeneration system Solution B from BDBiosciences, 5% acetonitrile and 0.05% DMSO). These are then seriallydiluted 1:1 (160 μL to 160 μL co-factor mix) for a total of 10 points. A10 μL aliquot of this final mixture is dispensed into 384 well assayplates and incubated for 10 minutes at 37° C. Enzyme and substrate mix(10 μL; 0.5 pmol CYP1A2/5 μM CEC; 1.0 pmol CYP2C9/75 MFC; 0.5 pmolCYP2C19/25 μM CEC; 1.5 pmol CYP2D6/1.5 μM AMMC; 1.0 pmol CYP3A4/50 μMBFC; or 1.0 pmol CYP3A4/40 μM BQ) is added to these assay plates. Assayplates are incubated at 37° C. (CYP1A2-15 min; CYP2C9-45 min; CYP2C19,2D6 and 3A4-30 min) and read in a Tecan Safire 2 plate reader (CYP1A2,2C19 and 3A4 409 ex/460 em; CYP2C9 and 2D6 409 ex/530 em). The signalversus compound concentration is used to determine the IC₅₀. The enzymesand substrates for this assay are obtained from BD Biosciences. Whileother factors are involved in determining CYP effects in vivo, compoundspreferably have IC₅₀ values of >5 μM, more preferably IC₅₀ values of >10μM.

The following table indicates the Cyp inhibition for exemplary compoundsaccording to the invention as indicated:

Compound Cyp IC₅₀ (μM) number 1A2 2C19 2C9 2D6 3A4(BFC) 3A4(BQ)P-3001 >10 >10 >10 >10 >10 >10 P-3004 >10 5-10 >10 >10 >10 >10P-3006 >10 >10 >10 >10 >10 NA P-3008 >10 <5 5-10 >10 5-10 NA P-3009 >10<5 >10 >10 5-10 NA P-3010 >10 >10 >10 >10 >10 >10P-3011 >10 >10 >10 >10 >10 >10 P-3012 >10 >10 >10 >10 >10 >10 P-30135-10 <5 >10 >10 >10 >10 P-3018 >10 >10 >10 >10 <5 >10 P-3019 >10<5 >10 >10 >10 >10 P-3039 >10 >10 >10 >10 >10 NAP-3040 >10 >10 >10 >10 >10 >10 P-3041 >10 >10 >10 >10 5-10 >10P-3043 >10 >10 >10 >10 >10 >10 P-3044 >10 >10 >10 >10 >10 >10 P-3048 >10<5 >10 >10 >10 >10 P-3049 >10 >10 >10 >10 >10 >10P-3050 >10 >10 >10 >10 >10 >10 P-3051 >10 >10 >10 >10 >10 >10 P-3052 >105-10 5-10 >10 >10 >10 P-3053 >10 >10 >10 >10 >10 >10 P-4001 >10<5 >10 >10 >10 NA P-4002 >10 >10 >10 >10 >10 >10P-4003 >10 >10 >10 >10 >10 >10 P-4004 >10 >10 >10 >10 >10 >10P-4005 >10 >10 >10 >10 >10 >10 P-4006 >10 >10 >10 >10 >10 >10P-4007 >10 >10 >10 >10 >10 >10 P-4008 >10 >10 >10 >10 5-10 >10P-4009 >10 5-10 >10 >10 >10 >10 P-4010 >10 >10 >10 >10 >10 >10P-4011 >10 >10 5-10 >10 5-10 >10 P-4012 >10 >10 >10 >10 >10 >10P-4013 >10 >10 <5 >10 >10 >10 P-4014 >10 >10 5-10 <5 5-10 >10P-4015 >10 >10 >10 >10 >10 >10 P-4016 >10 >10 >10 >10 >10 >10P-4017 >10 >10 >10 >10 >10 >10 P-4018 >10 <5 >10 >10 5-10 >10 P-4019 >105-10 >10 >10 5-10 >10 P-4022 >10 5-10 >10 5-10 5-10 >10 P-4023 >10<5 >10 5-10 <5 >10 P-4024 >10 >10 >10 >10 <5 >10 P-4025 >10 5-10 >10 >10<5 >10 P-4028 >10 5-10 5-10 >10 >10 >10 P-4029 >10 >10 >10 >10 >10 >10P-4030 >10 5-10 >10 >10 >10 >10 P-4031 >10 >10 >10 <5 >10 >10 P-40365-10 5-10 5-10 >10 5-10 5-10 P-4037 >10 >10 5-10 >10 5-10 5-10 P-40415-10 <5 5-10 >10 >10 5-10 P-4047 >10 >10 >10 >10 >10 >10P-4048 >10 >10 >10 >10 >10 >10 P-4049 >10 5-10 5-10 >10 >10 >10P-4050 >10 >10 >10 >10 >10 >10 P-4051 >10 >10 >10 >10 >10 >10P-4052 >10 >10 >10 >10 >10 >10 P-4053 >10 >10 >10 >10 >10 >10P-4054 >10 >10 >10 >10 >10 >10 P-4055 <10 <10 >10 >10 >10 >10 P-4056 >105-20 >10 >10 >10 >10 P-4057 >10 >10 >10 >10 >10 >10P-4058 >10 >10 >10 >10 >10 >10 P-4059 >10 >10 5-10 >10 >10 >10P-4060 >10 >10 >10 >10 >10 >10 P-4061 >10 >10 >10 >10 >10 >10P-4062 >10 >10 >10 >10 >10 >10 P-4063 >10 >10 >10 >10 >10 >10P-4064 >10 >10 >10 >10 >10 >10 P-4065 >10 >10 >10 >10 >10 >10P-4066 >10 >10 >10 >10 >10 5-10 P-4067 >10 5-10 >10 >10 >10 >10P-4068 >10 >10 >10 >10 >10 >10 P-4069 >10 5-10 >10 >10 5-10 >10P-4070 >10 >10 >10 >10 >10 >10 P-4071 >10 >10 >10 >10 >10 >10 P-4072 >10<10 5-10 5-10 >10 >10 P-4073 >10 5-10 >10 >10 >10 >10 P-4074 >105-10 >10 >10 >10 >10 P-4075 >10 5-10 >10 >10 >10 >10 P-4076 >105-10 >10 >10 >10 >5 P-4077 5-10 5-10 >10 >10 >10 >10 P-40785-10 >10 >10 >10 >10 >10 P-4079 >10 5-10 >10 >10 >10 >10P-4080 >10 >10 >10 >10 >10 >10 P-4081 >10 >10 >10 >10 >10 >10P-4082 >10 >10 >10 >10 >10 5-10 P-4083 >10 >10 >10 >10 >10 >10P-4084 >10 5-10 >10 >10 >10 >10 P-4087 >10 >10 >10 >10 >10 >10P-4088 >10 >10 >10 >10 >10 >10 P-4089 >10 >10 >10 >10 >10 >10P-4090 >10 >10 >10 >10 >10 >10 P-4091 >10 >10 >10 >10 >10 >10 P-4092 <5<5 <5 <5 >10 >10 P-4093 >10 >10 >10 >10 >10 >10 P-4094 <5 <5 <5<5 >10 >10 P-4095 >10 >10 >10 >10 >10 >10 P-4096 <5 <5 <5 <5 >10 5-10P-4097 <5 <5 <5 <5 >10 >10 P-4098 <5 <5 <5 <5 >10 >10 P-4099 <5 <5 <5<5 >10 <5 P-4100 <5 <5 <5 <5 >10 >10 P-4101 >10 5-10 5-10 >10 >10 >10P-4102 <5 <5 <5 <5 >10 >10 P-4103 <5 >10 >10 >10 >10 >10 P-4104 >105-10 >10 >10 >10 >10 P-4105 >10 >10 >10 >10 >10 >10 P-4106 <5 <5 <5<5 >10 >10 P-4107 <5 <5 <5 <5 >10 >10 P-4108 <5 <5 <5 <5 >10 >10P-4109 >10 5-10 5-10 >10 >10 >10 P-4110 <5 <5 <5 <5 >10 >10 P-4111 >105-10 5-10 >10 >10 5-10 P-4112 <5 <5 <5 <5 >10 >10P-4113 >10 >10 >10 >10 >10 >10 P-4114 >10 >10 >10 >10 >10 >10 P-4115 <5<5 <5 <5 >10 >10 P-4116 >10 >10 >10 >10 >10 >10 P-4117 5-10 >105-10 >10 >10 >10 P-4118 >10 >10 >10 >10 >10 >10P-4119 >10 >10 >10 >10 >10 >10 P-4120 <5 <5 <5 <5 >10 >10 P-4121 >105-10 >10 >10 >10 >10 P-4122 >10 >10 5-10 >10 >10 >10P-4123 >10 >10 >10 >10 >10 >10 P-4124 <5 <5 <5 <5 >10 >10P-4125 >10 >10 >10 >5 >10 >10 P-4126 <5 >10 >10 >10 <10 5-10 P-4127 >105-10 >10 >10 <5 <5 P-4128 >10 >10 >10 >10 >10 >10 P-4129 >10 >10 5-105-10 <5 <5 P-4130 >10 <5 >10 >10 <5 >10

Pharmacokinetic properties of compounds (including any solid forms orformulations thereof) are assessed in male Sprague Dawley rats or maleBeagle dogs. Rats are dosed daily with compound either by IV injectionsvia surgically implanted jugular catheters or by oral gavage (P0). Eachcompound is prepared as a 20 mg/mL stock solution in dimethyl sulfoxide,which is further diluted to provide the dosing stock at the desiredconcentration for the IV or PO formulations. For IV dosing, the dosingstock is diluted into a 1:1:8 mixture of Solutol®:ethanol:water. For POdosing, the dosing stock is diluted into 1% methylcellulose. In acassette format (or each compound, solid form thereof or formulationthereof is done individually), compounds are diluted to 0.5 mg/mL eachfor IV dosing and 0.4 mg/mL each for PO dosing and dosed at 1 mg/kg (2mL/kg) or 2 mg/kg (5 mL/kg), respectively. For IV dosed animals, tailvein blood samples are collected with lithium heparin anticoagulant at5, 15, 30, and 60 minutes and 4, 8, and 24 hours post dosing each day.For PO dosed animals, tail vein blood samples are collected with lithiumheparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hours post dosingeach day. Dogs are dosed daily by oral capsules in a suitableformulation at 50 mg/mL. Cephalic vein blood samples are collected withlithium heparin anticoagulant at 30 minutes, 1, 2, 4, 8 and 24 hourspost dosing each day. All samples are processed to plasma and frozen forlater analysis of each compound by LC/MS/MS. Plasma levels as a functionof time are plotted to assess the AUC (ng*hr/mL). Compounds according tothe present invention preferably show improved pharmacokineticproperties relative to previously described compounds, i.e. they havesubstantially higher values for one or more of AUC, Cmax and half-liferelative to previously described compounds.

Analysis of penetration of compound into the brain can be assessedsimilarly. Each compound is prepared as a 100 mg/mL stock solution indimethyl sulfoxide, as well as control compounds atenolol at 100 mg/mLand antipyrine at 50 mg/mL. In a cassette format, up to three testcompounds, along with atenolol and antipyrine, are combined, 180 μLeach, and added to 17.1 mL of 1% methylcellulose. The compounds are in asuspension that is administered in a single dose (10 mL per kg bodyweight) to 2 groups of CD rats (8-9 weeks, n=3 per group) by oralgavage, an additional group of rats dosed with vehicle only. One groupof compound treated rats is sacrificed at 2 hours post dosing, the othergroup at 6 hours. Plasma is collected in Li-heparin and the brains arecollected, cut into right and left hemispheres, weighed and flashfrozen. Brain homogenate (30%) and plasma samples are assessed byequilibrium dialysis using a 96 well equilibrium dialysis apparatus witha 5K MW cut off membrane (The Nest Group, Inc.) as per the vendor'sprotocol with the samples on one side of the dialysis membrane and anequal volume of 1×PBS on the other side. The apparatus is incubatedovernight at 37° C. on a plate rotator (The Nest Group, Inc.). Thecompound concentrations on both sides are analyzed by LC/MS/MS tocalculate the mass balance recovery. The concentration in the PBS sideis calculated using a standard curve generated for each compound. ThePBS concentration is the free compound concentration, while the sidewith the biological sample provides the concentration in plasma orbrain.

Example 17: Efficacy of Compounds in Combination with Standard-of-CareChemotherapeutic Agents in Four Human Cancer Cell Lines

Compounds of the invention, such as compounds of Formula I, incombination with a standard chemotherapeutic agent, such as5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin,paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed fortheir effectiveness in killing human tumor cells. Such assays are knownin the art, for example, as described in U.S. patent application Ser.No. 11/473,347, the disclosure of which are hereby incorporated byreference with respect to such assays.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art, which are encompassed within the spirit of theinvention, are defined by the scope of the claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof” and “consisting of” may be replaced with either of the other twoterms. Thus, for an embodiment of the invention using one of the terms,the invention also includes another embodiment wherein one of theseterms is replaced with another of these terms. In each embodiment, theterms have their established meaning. Thus, for example, one embodimentmay encompass a method “comprising” a series of steps, anotherembodiment would encompass a method “consisting essentially of” the samesteps, and a third embodiment would encompass a method “consisting of”the same steps. The terms and expressions which have been employed areused as terms of description and not of limitation, and there is nointention that in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

Also, unless indicated to the contrary, where various numerical valuesare provided for embodiments, additional embodiments are described bytaking any 2 different values as the endpoints of a range. Such rangesare also within the scope of the described invention.

Thus, additional embodiments are within the scope of the invention andwithin the following claims.

What is claimed is:
 1. A method for treating a subject with a disease orcondition selected from the group consisting of rheumatoid arthritis,osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemicsclerosis, demyelinating disorders, multiple sclerosis, Charcot MarieTooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease,Parkinson's disease, global ischemia, ulcerative colitis, Crohn'sdisease, immune thrombocytopenic purpura, atherosclerosis, systemiclupus erythematosis, myelopreparation for autologous transplantation,transplant rejection, glomerulonephritis, interstitial nephritis, Lupusnephritis, tubular necrosis, diabetic nephropathy, renal hypertrophy,type I diabetes, chronic pain, acute pain, inflammatory pain,neuropathic pain, bone pain, pain associated with cancer, surgery, orbone fracture, acute myeloid leukemia, melanoma, multiple myeloma,breast cancer, prostate cancer, pancreatic cancer, non-small cell lungcancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis,osteolytic bone metastases, brain metastases, gastrointestinal stromaltumors, and giant cell tumors, said method comprising administering tothe subject in need thereof an effective amount of a compound of FormulaIa:

or a salt thereof, wherein: Y₂ is —N═ and R¹⁵ is hydrogen; or Y₂ is—C(H)═ and R¹⁵ is fluoro or chloro; L₂ is —CH₂— or —C(O)—; Cy₂ iscycloalkyl optionally substituted with one or more R¹⁶; R¹⁴ is—N(R^(9a))(R^(9b)); R^(9a) is H and R^(9b) is selected from the groupconsisting of (i) H, lower alkyl, lower alkyl substituted with one ormore substituents independently selected from fluoro, lower alkylsubstituted with lower alkoxy, and lower alkyl substituted withhydroxyl, and (ii) cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl, each of which isoptionally substituted with one to three members independently selectedfrom lower alkyl, haloalkyl, lower alkoxy, and fluoro; or R^(9a) andR^(9b) together with the nitrogen to which they are attached form a 5-or 6-membered ring having from 0 to 1 additional heteroatom selectedfrom O, N, or S, each of which is optionally substituted with one tothree members independently selected from lower alkyl, haloalkyl, loweralkoxy, and fluoro; and each R¹⁶ is independently selected from thegroup consisting of fluoro, —OH, lower alkyl optionally substituted withone or more substituents independently selected from fluoro, and loweralkoxy optionally substituted with one or more fluoro.
 2. The method ofclaim 1, wherein L₂ is —C(O)—.
 3. The method of claim 2, wherein Y₂ is—C(H)═.
 4. The method of claim 1, wherein Cy₂ is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cyclopentyl, each of which isoptionally substituted with from 1 to 3 R¹⁶.
 5. The method of claim 1,wherein each R¹⁶ is F.
 6. The method of claim 1, wherein R^(9b) is loweralkyl.
 7. The method of claim 1, wherein R^(9b) is lower alkylsubstituted with one or more fluoro.
 8. The method of claim 1, whereinthe compound is selected from the group consisting of:

or a salt thereof.
 9. The method of claim 1, wherein the compound is:

or a salt thereof.
 10. The method of claim 1, wherein the compound is:

or a salt thereof.
 11. The method of claim 1, wherein the compound is:

or a salt thereof.
 12. The method of claim 1, wherein the compound is:

or a salt thereof.
 13. The method of claim 1, wherein the compound is:

or a salt thereof.
 14. The method according to any of the precedingclaims, wherein the disease or condition is chronic pain, acute pain,inflammatory pain, neuropathic pain, or bone pain.
 15. The methodaccording to claim 14, wherein the disease or condition is inflammatorypain.
 16. The method according to claim 1, wherein the disease orcondition is pain associated with cancer, surgery, or bone fracture. 17.The method according to claim 1, wherein the disease or condition ispancreatic cancer.
 18. The method according to claim 1, wherein thedisease or condition is gastrointestinal stromal tumors.
 19. The methodaccording to claim 1, wherein the disease or condition is non-small celllung cancer.